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Budesonide enema for the treatment of active, distal ulcerative colitis and proctitis: A dose-ranging study
GASTROENTEROLOGY 1998;115:525–532
ALIMENTARY TRACT Budesonide Enema for the Treatment of Active, Distal Ulcerative Colitis and Proctitis: A Dose-Ranging Study STEPHEN B. HANAUER,* MALCOLM ROBINSON,‡ RONALD PRUITT,§ AUDREY J. LAZENBY,\ TORE PERSSON,¶ LARS–GORAN NILSSON,¶ KAREN WALTON–BOWEN,# LLOYD P. HASKELL,# and JEFFREY G. LEVINE# for the U.S. BUDESONIDE ENEMA STUDY GROUP *Department of Medicine, University of Chicago, Chicago, Illinois; ‡Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; §Department of Medicine, Nashville Medical Research Institute, Nashville, Tennessee; \Department of Pathology, The Johns Hopkins University, Baltimore, Maryland; ¶Departments of Clinical Research and Development and Biostatistics and Data Processing, Astra Draco AB, Lund, Sweden; and #Departments of Biostatistics and Clinical Research, Astra USA Inc., Westborough, Massachusetts
Background & Aims: Budesonide is a highly potent topical glucocorticosteroid that is characterized by low systemic availability as a result of high first-pass hepatic metabolism. The aim of this study was to evaluate the efficacy and safety of three doses of an enema preparation of budesonide in patients with active distal ulcerative colitis/proctitis. Methods: In a double-blind multicenter trial, 233 patients were randomized to receive either a placebo enema or budesonide enema at a dose of 0.5 mg/100 mL, 2.0 mg/100 mL, or 8.0 mg/100 mL. The primary efficacy variables were an improvement of sigmoidoscopic inflammation grade, total histopathology score, and remission rates. Effects on cortisol concentrations were also assessed. Results: After 6 weeks of treatment, there was significant improvement in sigmoidoscopy and histopathology scores in the budesonide 2.0-mg and 8.0-mg dose groups compared with placebo. Remission was achieved in 19% of patients in the 2.0-mg budesonide group (P # 0.050) and 27% of patients in the 8.0-mg budesonide group (P # 0.001) compared with 4% in the placebo group. More than 90% of all budesonide patients had a normal adrenocorticotropin (ACTH)stimulated cortisol response at the last visit. The budesonide enemas were well tolerated. Conclusions: Budesonide enema is both effective and safe for the treatment of active distal ulcerative colitis/proctitis. A dose of 2.0 mg/100 mL budesonide is the lowest effective dose.
lcerative colitis is a chronic inflammatory bowel disorder of unknown origin that is characterized by short-term and long-term inflammation of the bowel. The proximal extent of the colonic mucosal inflammation varies among individuals, but almost always involves the rectum.1 Anti-inflammatory agents such as mesalamine and glucocorticosteroids administered orally or as an
U
enema are the most common forms of treatment.2,3 Enemas have the advantage of treating proctitis and left-sided disease locally because they may reach to (but seldom beyond) the splenic flexure. Unfortunately, conventional steroid enemas may have unwanted glucocorticosteroid side effects because of high systemic exposure.4 Budesonide is a glucocorticosteroid that is structurally related to 16a-hydroxyprednisolone. It has a high topical anti-inflammatory effect due to its high affinity for the glucocorticosteroid receptor and low systemic activity by virtue of its extensive first-pass hepatic metabolism (with resultant metabolites virtually devoid of significant glucocorticosteroid activity).4,5 Budesonide has been used in the treatment of asthma, allergic rhinitis, ulcerative colitis, and Crohn’s disease (in an oral formulation designed to be released in the ileum and proximal colon), with efficacy similar to that of conventional steroids but with few adverse events and significantly less impact on the hypothalamic-pituitary-adrenal axis.2,4,6–9 The suspension enema formulation of budesonide (Entocort enema; Astra Draco AB, Lund, Sweden) is designed to deliver the drug to the distal colon. Previous studies have shown it to be as effective as other steroid and mesalamine enemas.2,7–10 The present study was designed to assess the efficacy and safety of three doses of budesonide enema vs. placebo enema when administered once daily at bedtime for 6 weeks in the treatment of active distal ulcerative colitis.
Patients and Methods Patient Selection Eligible patients were outpatients older than 18 years with newly diagnosed or ongoing active, distal (to splenic r 1998 by the American Gastroenterological Association 0016-5085/98/$3.00
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flexure) ulcerative colitis extending from 5 to 50 cm from the anal ring. Patients were required to have a sigmoidoscopic inflammation grade score of 2 or greater at inclusion (see Study Design). Symptoms of active distal ulcerative colitis/proctitis were to include at least one of the following changes in bowel function: frequency and urgency of stools, presence of diarrhea, or presence of grossly visible blood. Significant exclusion criteria included (1) pregnant or nursing women; (2) presence of symptomatic, organic disease of the gastrointestinal tract (with the exception of rectal hemorrhoids or hiatal hernia); (3) presence of any significant laboratory abnormalities; (4) a history of active ulcerative colitis proximal to the splenic flexure; (5) hypersensitivity to glucocorticosteroids; and (6) ova or parasites, pathogens, and/or toxins (Clostridium difficile) found in stools. Topical steroids were not allowed within the previous 2 weeks before screening, and systemic steroids (orally or rectally administered) were not allowed within the preceding 4 weeks before screening. Any rectally administered drug for ulcerative colitis had to be discontinued 2 weeks before randomization. Patients were allowed to take oral mesalamine products as long as their dose had remained constant during the 2 months before randomization; this dose could not be changed during the study period. Initiation of treatment with an oral mesalamine product was not allowed during the week before screening or during the study. The study was approved by the institutional review board at each center or through a central review board and was conducted in accordance with the Declaration of Helsinki.
Study Medication Budesonide enema was manufactured by Astra Draco AB (Lund, Sweden) and consisted of dispersible tablets containing 0.58, 2.3, or 9.2 mg budesonide, which were then dissolved in 115 mL of 0.9% saline solution (the enema vehicle was manufactured by Astra Pharmaceutical Production, So¨derta¨lje, Sweden) by the patient just before use. Because the average residual volume in the enema bottle is 15 mL, the actual dose of budesonide administered was 0.5, 2.0, or 8.0 mg/100 mL. All tablets were identical in appearance. The reference drug was a placebo tablet that was identical in appearance to the budesonide tablets and dispersed in an identical enema vehicle.
Study Design The study was a 6-week randomized, double-blind, multicenter trial performed at 33 centers throughout the United States from July 1991 to January 1993. After a 1-week screening period, 233 patients were randomized to three treatment arms and one placebo arm. All patients were required to sign an informed consent. At randomization, patients were assigned to one of the following four study arms: placebo enema or 0.5, 2.0, or 8.0 mg/100 mL budesonide enema. All enemas were given once daily at bedtime. The patients were instructed to retain the enema for as long as possible, preferably over night. A complete medical history was taken, and a complete physical examination was performed during the screening
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period. A second complete physical examination was again performed at week 6. Stool samples were obtained during the screening period to detect pathogens and C. difficile toxin unless done within 1 month before screening flexible sigmoidoscopy. Flexible sigmoidoscopy was performed during the screening period and at weeks 2, 4, and 6. This was done to evaluate the extent of the inflammation (measured from the anal ring in centimeters), to obtain tissue for histopathology (biopsies were performed only during the screening flexible sigmoidoscopy and at the end of the study at week 6), and to assess the macroscopic appearance of the most severely inflamed area of mucosa (sigmoidoscopic inflammation grade). Sigmoidoscopic inflammation was graded on a 4-point scale as follows: 0, normal mucosa; 1, edema and/or loss of visible mucosal vascularity, granularity; 2, friability (defined as visible, induced bleeding on examination), petechiae; and 3, spontaneous hemorrhage, visible ulcers. Biopsy specimens for histology were obtained from a distance between 5 and 10 cm from the anal ring. Two samples were obtained from the same level at each sigmoidoscopy and labeled only with a code number. All biopsy specimens were evaluated by the same pathologist (A.J.L.), who was blind to the treatment allocation. Biopsy specimens were histologically graded for active inflammation, chronic inflammation, and crypt distortion (Table 1). This scale is similar to that developed by Truelove and Richards.11 The total histopathology score was derived from the sum of the above three components (active inflammation, chronic inflammation, and crypt distortion). A colonoscopy was performed at screening if the upper margin of the affected area could not be seen during flexible sigmoidoscopy. Colonoscopy performed within 1 month before screening could be used in lieu of a colonoscopy at screening if detailed information on the results were available. At each visit (screening, week 2, week 4, and week 6), the physician, with the assistance of patient diary cards (see below), assessed the patient for symptoms of colitis (diarrhea, abdominal pain, intermittent tenesmus, and rectal bleeding; the investigator assessment of ulcerative colitis symptom score). Global evaluation (investigator global evaluation) was also performed based on a 5-point scale as follows: 0, normal or in remission; 1, mild (symptoms present, but not bothersome); 2, moderate (symptoms bothersome); 3, severe (symptoms interfere with normal activities); and 4, incapacitating (symptoms do not allow patient to continue normal activities). Patients were also required to fill out daily diary cards and record their daily rating of quality of life (Global Quality of Life) using a 4-point scale (0, excellent; 1, good; 2, fair; and 3, poor), the number of formed stools with and without visible blood, and the number of episodes of diarrhea with and without blood. They also recorded symptoms of urgency, abdominal pain, and painful bowel evacuations on a 0 (none) to 4 (incapacitating) scale. Laboratory evaluations included hematology, blood chemistry, serum pregnancy test (females only), urinalysis (all done during screening and at week 6), and morning basal and
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Table 1. Histopathology Evaluation Inflammation grade Active inflammation
Score 0
1
2
3
Chronic inflammation
0
1
2
Crypt distortion
0
1
2
3
Intensity
Histological criteria
Normal
Neutrophils not present in crypt or surface epithelium and no exudate, erosion, or ulceration Low grade Neutrophils present transmigrating through the crypt epithelium or within crypt lumina in ,20% of crypts; no erosions or ulcers Moderate Neutrophilic infiltration in .20% of crypts or presence of erosions (loss of superficial mucosa accompanied by fibroinflammatory exudate) High grade Presence of ulcers (loss of the entire thickness of mucosa and recognized as fragments of inflamed gradation tissue) No increase Number of chronic inflammatory cells within normal limits and present primarily in the superficial lamina propria Moderate Mononuclear cells present in moderate numbers and aggregated between crypts at the base of the lamina propria Severe Marked increase in chronic inflammation shown by sheets of chronic cells None Crypts had normal outlines with only artifactual irregularities Mild Scattered or rare crypts showing irregular (bent, forked) outline Moderate Approximately 25%–50% of crypts with an irregular outline Severe More than 50% of crypts with an irregular outline
ACTH-stimulated cortisol concentrations (done at randomization before receiving study medication and at week 6). Basal and ACTH-stimulated cortisol blood samples were obtained just before and 1 hour after intramuscular injection of Cortrosyn, 0.25 µg (Organon, NJ). All analyses were performed at one central reference laboratory (SmithKline Beecham Clinical Laboratories). Adverse events were recorded at each visit. The likelihood of the relationship to blinded medication was rated as none,
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unlikely, possible, probable, or highly probable. Adverse events were also evaluated as possible glucocorticosteroid-associated side effects.
Statistical Analysis A sample size of 200 patients was based on the expected differences in change from baseline in sigmoidoscopic inflammation score compared with placebo. The standard deviation of change in sigmoidoscopy score was assumed to be 1, baseline score was 2 or 3, and hypothesis testing was to be completed using two-tailed tests at the 0.050 level of significance. With 50 patients per treatment group, the power was 80% if the true difference between two treatments was 0.58. For each efficacy variable, the analysis started with an overall comparison by analysis of variance or x2 test. When this was significant the groups were compared pairwise. All P values for paired comparisons were for the two-sided Student’s t test or the equivalent x2 without correction for multiplicity. The primary efficacy variables included the mean change from baseline for the sigmoidoscopic inflammation grade, total histopathology score (sum of all three components), and remission rate. The primary definition of remission was rigorously defined as three or less bowel movements per day; no blood in stools; no symptoms of urgency, abdominal pain, or painful evacuations; and a sigmoidoscopic inflammation grade score of 0. Patients had to achieve all of these criteria for the 2 days preceding the visit to be considered in remission. In addition, there were two secondary definitions of remission that included sigmoidoscopic inflammation grade score of 0 and investigator global evaluation score of 0 or a decrease of 2 or more points from baseline. Secondary efficacy variables included changes in the investigator assessment of active ulcerative colitis symptoms, investigator global evaluation, global quality of life, and improvement in the extent of the lesion (in centimeters). Safety variables included changes in basal plasma and ACTH-stimulated cortisol concentrations from baseline and the percent of patients with normal basal cortisol values; normal response to ACTH stimulation; and the percentage of patients who had both normal basal and normal ACTHstimulated plasma cortisol response. Normal basal cortisol was defined as $150 nmol/L. Normal ACTH-stimulated cortisol response was defined as a poststimulated cortisol value $400 nmol/L and/or an increase of $200 nmol/L. The incidence of reported adverse events was also considered. Two approaches to analysis were used: intent-to-treat and per protocol analyses. The intent-to-treat population included all patients who received double-blind medication, had baseline data, and had double-blind observation for at least one visit. Because there were no significant differences between these analyses, only the intent-to-treat analysis is presented. To determine changes from the baseline, the on therapy data was subtracted from the baseline data. Thus, the larger the positive number, the greater the change from baseline and the greater the improvement. Mean changes from baseline for both primary and secondary variables were analyzed using analysis of
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variance techniques that included baseline, center, and treatment as factors in the model. Remission rates and percent of patients with normal cortisol values were analyzed using categorical data techniques. For missing values, the ‘‘last value carried forward’’ procedure was used from the first follow-up visit (week 2). Although week 6 was the primary end point, information for week 2 and week 4 is also included where applicable.
Results Patients A total of 233 patients were randomized (33 patients who were in the screening phase at the time recruitment ended were randomized), with 60 to the placebo group, 57 to the 0.5 mg/100 mL budesonide group, 56 to the 2.0 mg/100 mL budesonide group, and 60 to the 8.0 mg/100 mL budesonide group. Table 2 shows the patient demographic data, number of patients using products containing mesalamine, and baseline data for the primary and secondary efficacy criteria. There Table 2. Baseline Data Budesonide dose Placebo Patient characteristics No. of patients Age (yr) #40 .40 Mean Sex Male Female Race White Black Hispanic Other SIG Grade 2 Grade 3 No. of patients using mesalamine products Mean baseline scores Sigmoidoscopic inflammation grade Total histopathology Investigator assessment of ulcerative colitis symptoms Investigator global evaluation Patient global quality of life Extent of lesion (cm)
0.5 mg
2.0 mg
8.0 mg
60
57
56
60
35 25 43
34 23 39
30 26 42
38 22 40
30 30
32 25
28 28
36 24
54 3 3 0
53 2 1 1
46 6 3 1
54 3 2 1
36 21
25 30
22 32
37 23
22
19
29
20
2.37 5.55
2.54 4.67
2.59 5.36
2.38 5.56
5.69
5.54
5.87
5.85
2.06
1.95
1.95
1.93
1.74 30.80
1.60 27.10
1.45 27.80
1.58 26.40
SIG, sigmoidoscopic inflammation grade.
were no important differences between groups. Table 3 shows the details of the patient discontinuations. There were more discontinuations from the placebo and budesonide 0.5-mg dose groups than from the budesonide 2.0-mg and 8.0-mg dose groups. Primary Efficacy End Points The sigmoidoscopic inflammation grade significantly improved in the 2.0-mg and 8.0-mg dose groups at week 6 (P # 0.001) compared with placebo. The 0.5-mg dose was not significantly different from placebo. Significance for the 2.0-mg group was reached at week 4 (P # 0.010), and significance for the 8.0-mg dose was reached at weeks 2 and 4 (P # 0.001) compared with placebo (Figure 1). Total histopathology score improved significantly at week 6 for the 2.0-mg group (P # 0.050) and for the 8.0-mg group (P # 0.001) compared with placebo. The 0.5-mg dose was not significantly different from placebo (Figure 2). Remission rates (as defined by the primary definition) were significant for the 2.0-mg dose at week 6 (P # 0.050) with 19% of patients in remission and for the 8.0-mg dose at week 6 (P # 0.001) with 27% of patients in remission, compared with placebo with 4% of patients in remission. Again, the 0.5-mg dose (7% of patients in remission) was not significantly different from placebo (Figure 3). There was no significant difference between the 2.0-mg and the 8.0-mg doses for any of the primary efficacy variables at any evaluated time point. Secondary Efficacy End Points Investigator assessment of ulcerative colitis symptoms was derived from the sum of four criteria. The mean change from baseline was significant for the 2.0-mg and 8.0-mg dose groups for each individual criteria as well as the total symptom score (Figure 4). The investigator’s global evaluation score, patient’s global quality of life score, and extent of the lesion all improved significantly by week 6 for the 2.0-mg and 8.0-mg dose groups (Table 4). There were also two secondary definitions of remission. For sigmoidoscopic inflammation grade score of 0, 15.7% of patients in the placebo group, 19.6% of patients in the 0.5-mg group (not statistically significantly different than placebo), 35.2% of patients in the 2.0-mg group (P # 0.010 vs. placebo), and 44.3% of patients in the 8.0-mg group (P # 0.001 vs. placebo) were in remission at week 6. When remission was defined as an investigator global evaluation grade of 0 or a decrease of 2 or more points from baseline, 41.5% of patients in the 2.0-mg group (P # 0.050) and 55.2% of patients in the 8.0-mg group (P # 0.001) were in
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Table 3. Patient Discontinuations Budesonide dose Reason for discontinuation
Placebo (n 5 60)
0.5 mg (n 5 57)
2.0 mg (n 5 56)
8.0 mg (n 5 60)
Total (n 5 233)
Inadequate response Protocol violations Adverse experiences Unsatisfactory compliance Withdrew consent Lost to follow-up Total discontinued
17 (28) 2 (3) 3 (5) 1 (2) 1 (2) 0 (0) 24 (40)
12 (21) 1 (2) 0 (0) 2 (4) 0 (0) 1 (2) 16 (28)
3 (5) 2 (4) 2 (4) 2 (4) 0 (0) 2 (4) 11 (20)
9 (15) 1 (2) 0 (0) 0 (0) 2 (3) 0 (0) 12 (20)
41 (18) 6 (2) 5 (2) 5 (2) 3 (1) 3 (1) 63 (27)
NOTE. Number (%) of patients discontinued from the trial.
remission compared with 20.0% of patients in the placebo group at week 6. Thirty-three percent (33.2%) of the patients in the 0.5-mg group were in remission at week 6, which was not statistically different from placebo. Cortisol and Safety Ninety-four percent of patients in the 0.5-mg group (not significant), 87% of patients in the 2.0-mg group (P # 0.050), and 64% of patients in the 8.0-mg group (P # 0.001) had normal basal cortisol values compared with 98% of patients in the placebo group at week 6. Ninety-six percent of patients in the 0.5-mg dose group (not significant), 91% of patients in the 2.0-mg dose group (P # 0.050), and 92% of patients in the 8.0-mg dose group (P # 0.050) had a normal ACTHstimulated cortisol response compared with 100% of patients in the placebo group at week 6. Ninety-one percent of patients in the 0.5-mg dose group (not significant), 78% of patients in the 2.0-mg dose group (P # 0.010), and 59% of patients in the 8.0-mg dose
Figure 1. Sigmoidoscopic inflammation grade. The adjusted mean changes from baseline show the improvement in inflammation grade for each treatment arm at each evaluated time point. Budesonide enema at 2.0 mg significantly improved sigmoidoscopic inflammation after 4 weeks (**P # 0.010 vs. placebo) and 6 weeks (***P # 0.001 vs. placebo). Budesonide enema at 8.0 mg significantly improved sigmoidoscopic inflammation after 2, 4, and 6 weeks (***P # 0.001 vs. placebo).
group (P # 0.001) had both normal basal cortisol values and normal ACTH-stimulated cortisol response compared with 98% of patients in the placebo group at week 6. When the mean changes in basal values from baseline were compared, there was no statistically significant difference between the placebo and the 0.5-mg and 2.0-mg dose groups, whereas there was a statistically significant difference between placebo and the 8.0-mg dose group (P # 0.001). Both the 2.0-mg and 8.0-mg dose groups had a statistically significant larger mean change from baseline ACTH-stimulated cortisol values compared with placebo (P # 0.001) at week 6. The 0.5-mg dose group was not different from placebo for the ACTH-stimulated cortisol values (Table 4). No clinically relevant possible glucocorticosteroid side effects were reported. The proportion of patients with one or more adverse events was not statistically significantly different between the groups for all events regardless of relationship to study drug (none, unlikely, possible, probable, or highly probable). The number and percent of adverse events that were reported as possibly related to study drug (unlikely, possible, probable, or highly probable)
Figure 2. Total histopathology score at week 6. Mean change from baseline showing the improvement in total histopathology score (the sum of the active and chronic inflammation and crypt distortion components). Budesonide enema at 2.0 and 8.0 mg significantly improved total histopathology scores after 6 weeks of treatment (*P # 0.050 vs. placebo and ***P # 0.001 vs. placebo, respectively).
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Cushing’s syndrome. For all adverse events regardless of relationship and for adverse events related to study medication, the most frequently reported adverse events were headache, back pain, dyspepsia, and nausea. There was one death during this study that resulted from an acute myocardial infarction in a patient on placebo enema.
Discussion
Figure 3. Percent of patients in remission (primary definition). After 6 weeks of treatment, both budesonide enema at 2.0 mg and 8.0 mg induced remission in a higher percentage of patients compared with placebo (*P # 0.050 and ***P # 0.001, respectively). For week 6, 95% confidence intervals are shown in parentheses. Remission was defined as including all of the following during the 2 days before physician visit: three or less bowel movements per day; no blood in stool; no symptoms of urgency, abdominal pain, or painful evacuations; and sigmoidoscopic inflammation grade of 0.
were also not different between study groups: 18 patients (30%) in the placebo group, 21 patients (37%) in the 0.5-mg budesonide group, 20 patients (36%) in the 2.0-mg group, and 24 patients (40%) in the 8.0-mg group experienced drug-related adverse events. Serious adverse events were few with 4 patients (6.7%) in the placebo group and 3 patients (1.7%) in the budesonide groups (all budesonide groups combined). One (1.7%) patient in the budesonide 8.0-mg group had an event that was reported as adrenal insufficiency. Four patients (3.3%) in the placebo group and 2 (3.3%) in the 8.0-mg budesonide group had an event that was reported as
Figure 4. Total investigator assessment of ulcerative colitis symptom score. Mean change from baseline showing improvement in the sum of the ulcerative colitis symptom score (sum of diarrhea, abdominal pain, intermittent tenesmus, and rectal bleeding). Budesonide enema at 0.5 mg significantly improved ulcerative colitis symptom scores at week 2 and week 6 (*P # 0.050) compared with placebo. Budesonide enema at 2.0 mg and 8.0 mg significantly improved colitis symptom scores at week 2 (**P # 0.010 and ***P # 0.001, respectively) and week 4 and week 6 (***P # 0.001) compared with placebo.
Rectally administered steroids for distal ulcerative colitis/proctitis have been used extensively for more than 30 years. Unfortunately, high systemic availability of conventional steroids has the disadvantage of affecting the hypothalamic-pituitary-adrenal axis and inducing glucocorticosteroid side effects. Prolonged use of these enemas may be accompanied by these undesirable effects.8,12 Budesonide is in a new class of glucocorticosteroids that have a high topical effect as well as a high first-pass hepatic metabolism with low systemic availability.4 Budesonide enema reaches its maximum spread in approximately 15 minutes.13 The drug is nearly 100% absorbed into the portal circulation within 3–4 hours of administration.5 Approximately 85% of budesonide undergoes first-pass metabolism in the liver with a resulting systemic availability of about 15%.5 This dose-ranging study showed dose-related efficacy of budesonide enema compared with placebo, which is in agreement with observations of an earlier dose-ranging study.9 Budesonide (0.5 mg/100 mL) was not significantly different from placebo for any of the primary variables and many of the secondary variables. In contrast, 2.0 mg/100 mL budesonide and 8.0 mg/100 mL budesonide were consistently superior to placebo for all the primary and secondary efficacy variables. Efficacy was seen as early as 2 weeks after initiation of treatment with continued improvement noted throughout the 6 weeks. For the primary efficacy variables, the 2.0-mg dose was not statistically significantly different from the 8.0-mg dose; however, it should be noted that this study was not designed to detect a difference between these active groups. The low primary remission rate in this study may be explained by the rigorous criteria the patient had to meet to be considered in remission. This resulted in remission rates of 4%, 7%, 19%, and 26% for placebo and 0.5 mg, 2.0 mg, and 8.0 mg budesonide, respectively. This stringent definition produced remission rates that are lower than that usually seen with placebo, which is about 30%.14 With the less strict secondary remission criteria, remission rates were closer to expected ones. In a similarly designed study comparing 2 mg/100 mL budesonide enema to placebo and Cortenema (Solvay Pharmaceuticals, Marietta, GA), the same strict criteria for primary
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Table 4. Investigator Assessment, Secondary Efficacy Variables, and Cortisol Data Budesonide dose
Criteria Investigator assessment of ulcerative colitis symptoms Diarrhea Abdominal pain Intermittent tenesmus Rectal bleeding Total (sum of all four) Secondary efficacy variables at week 6 Investigator global evaluation score Global quality of life score Extent of lesion (cm) Cortisol data Baseline cortisol (nmol/L) Basal ACTH-stimulated Week 6 cortisol (nmol/L) Basal ACTH-stimulated Percent with normal cortisol at week 6 d Basal ACTH-stimulated Both
Placebo (n 5 59)
0.5 mg (n 5 57)
2.0 mg (n 5 55)
8.0 mg (n 5 60)
0.08 0.17 0.13 0.23 0.60
0.42 a 0.35 0.61 b 0.39 1.76 a
0.55 b 0.62 b 0.62 b 0.84 c 2.63 c
0.53 b 0.46 a 0.70 c 0.87 c 2.59 c
0.28 0.04 4.40
0.68 a 0.39 a 5.80
0.88 c 0.53 b 11.00 a
1.10 c 0.57 c 13.90 c
407 729
415 721
382 683
369 698
385 739
393 702
322 583 c
246 c 529 c
98 (94–100) 100 (99–100) 98 (94–100)
94 (86–100) 96 (90–100) 91 (83–99)
87 a (78–97) 91 a (83–99) 78 b (66–90)
64 c (51–77) 92 a (85–100) 59 c (45–73)
NOTE. Individual and total adjusted mean change from baseline scores at week 6 for the investigator assessment of symptoms. The adjusted mean change from baseline for the improvement in the remainder of the secondary efficacy variables. Mean basal and ACTH-stimulated cortisol data at baseline and at week 6 are shown. The percentage of patients with normal values for basal cortisol, ACTH-stimulated cortisol response, and the percentage of patients who had both normal basal cortisol and normal ACTH-stimulated cortisol responses are shown at week 6. aP # 0.050 vs. placebo. bP # 0.010 vs. placebo. cP # 0.001 vs. placebo. d95% confidence intervals are shown in parentheses.
remission was used.15 In that study, the percentage of patients achieving remission was 16% for budesonide enema, 11% for Cortenema, and 10% for placebo. Although the results did not reach statistical significance, the low remission rates are consistent with the present study. The fact that histopathology scores in the present study improved significantly is also of importance because biopsy healing tends to lag behind macroscopic healing.16 It has also been suggested that symptoms may correlate more with macroscopic findings than histopathology findings17; however, even sigmoidoscopic improvement may lag behind symptomatic improvement.18 Thus the significant improvement of all of these criteria (histopathology, sigmoidoscopic inflammation, and symptoms) in this study is further evidence of the efficacy of budesonide enema. A dose-related effect on basal cortisol and ACTHstimulated cortisol values was also found. Budesonide at 0.5 mg/100 mL had no significant effect on the hypothalamic-pituitary-adrenal axis compared with placebo. Budesonide at 8.0 mg/100 mL had the greatest effect on the hypothalamic-pituitary-adrenal axis with little improved efficacy over the 2.0-mg dose. During the 6-week study, the dose-related reduction of basal cortisol and
ACTH-stimulated cortisol values were not associated with any clinically significant glucocorticosteroid side effects. More than 90% of patients treated with budesonide enema (any dose) had a normal ACTH-stimulated cortisol response at week 6, indicating that adrenal function was not severely adversely affected by budesonide enema in doses up to 8.0 mg/100 mL. Other studies comparing prednisolone enema with budesonide enema have shown an even lesser effect of budesonide enema on the hypothalamic-pituitary-adrenal axis. In these studies, a significant effect by prednisolone, but not by budesonide, was seen.2,8,9 In one of these studies,2 the treatment period was 8 weeks with patient evaluations at 2, 4, and 8 weeks. Clinical remission was seen as early as 4 weeks and doubled by 8 weeks (both the budesonide and prednisolone groups), but with a significantly larger plasma cortisol suppression effect in the prednisolone group.2 Thus the apparent lack of adrenal suppression, even when used for a prolonged time of 8 weeks, would seem to be important. Budesonide enema at a dose of 2.0 mg/100 mL has also been compared with a 4-g mesalamine enema10 and a 1-g mesalamine enema19 with similar efficacy and adverse event profiles.
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Budesonide enema was well tolerated and safe. The number of patients experiencing adverse events (including serious adverse events) and the type and frequency of adverse events were similar for all doses of budesonide enema and placebo enema. The number of patients discontinuing the study was highest in the placebo and the 0.5 mg/100 mL budesonide groups and was mostly a result of inadequate response. In conclusion, budesonide enemas at 2.0 and 8.0 mg/100 mL were both clinically and statistically significantly superior to placebo in the treatment of active distal ulcerative colitis/proctitis. Budesonide enema had little effect on the hypothalamic-pituitary-adrenal axis and was safe and well tolerated. On the basis of this information, it seems that 2.0 mg/100 mL budesonide is the optimal dose for efficacy in association with little effect on the hypothalamic-pituitary-adrenal axis.
References 1. Kirsner JB. The historical basis of the idiopathic inflammatory bowel diseases. Inflamm Bowel Dis 1995;1:2–26. 2. Lo¨fberg R, Thomsen O, Langholz E, Schio¨ler R, Danielsson Å, Suhr O, Graffner H, Påhlman L, Matzen P, Mo¨ller-Petersen JF, Halvorsen L, Hovdenak N, Willen R, Persson T, Seidegård C. Budesonide versus prednisolone retention enemas in active distal ulcerative colitis. Aliment Pharmacol Ther 1994;8:623–629. 3. Sutherland LR, Martin F, Greer S, Robinson M, Greenberger N, Saibil F, Martin T, Sparr J, Prokipchuk E, Borgen L. 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis proctosigmoiditis, and proctitis. Gastroenterology 1987;92:1894– 1898. 4. Rutgeerts P. Budesonide enemas for topical therapy of ulcerative colitis. Can J Gastroenterol 1990;4:415–416. 5. Dahlstrom K, Edsbacker S, Kallen A. Rectal pharmacokinetics of budesonide. Eur J Clin Pharmacol 1996;49:293–298. 6. Greenberg GR, Feagan BG, Martin F, Sutherland L, Thomson A, Williams C, Nilsson L-G, Persson T. Oral budesonide for active Crohn’s disease. N Engl J Med 1994;331:836–841. 7. Porro GB, Prantera C, Campieri M, Petrillo M, Campanini MC, Gionchetti P, Grandinetti G, Mangiarotti R, Brunetti G, Ranzi T. Comparative trial of methylprednisolone and budesonide enemas in active distal ulcerative colitis. J Gastroenterol Hepatol 1994;6: 125–130. 8. Thomsen O, Andersen T, Langholz E, Lo¨fberg R, Malchow-Mo¨ller A, Matzen P, Nordstro¨m H, Persson T. Lack of adrenal gland suppression with budesonide enema in active distal ulcerative colitis: a prednisolone-controlled 8-week study. Eur J Gastroenterol Hepatol 1994;6:507–511. 9. The Danish Budesonide Study Group. Budesonide enema in distal ulcerative colitis: a randomized dose-response trial with prednisolone enema as positive control. J Gastroenterol 1991;26:1225– 1230. 10. Lamers C, Meijer J, Engels L, Van Heuverzwijn R, Cortot A, Viteau JM, Elewaut A, Belaiche J, Froguel E, Modigliani R. Comparative study of the topically acting glucocorticosteroid budesonide and a 5-ASA enema for proctitis and proctosigmoiditis (abstr). Gastroenterology 1991;100:A223. 11. Truelove SC, Richards WCD. Biopsy studies in ulcerative colitis. BMJ 1956;1:1315–1318. 12. Lee DAH, Taylor GM, James VHT, Walker G. Plasma prednisolone levels and adrenocortical responsiveness after administration of
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13.
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16. 17.
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prednisolone-21 phosphate as a retention enema. Gut 1979;20: 349–355. Nyman-Pantelidis M, Nilsson Å, Wagner ZG, Borgå O. Pharmacokinetics and retrograde colonic spread of budesonide enemas in patients with distal ulcerative colitis. Aliment Pharmacol Ther 1994;8:617–622. Meyers S, Janowitz HD. The ‘‘natural history’’ of ulcerative colitis: an analysis of the placebo response. J Clin Gastroenterol 1989; 11:33–37. Bayless T, Snisnky C. Budesonide enema is an effective alternative to hydrocortisone enema in active distal ulcerative colitis (abstr). Gastroenterology 1995;108:A778. Truelove SC, Witts LJ. Cortisone in ulcerative colitis: final report on a therapeutic trial. BMJ 1955;2:1041–1044. Powell-Tuck J, Fay DW, Buckell NA, Wadsworth J, Lennard-Jones JE. Correlation between defined sigmoidoscopic appearances and other measures of disease activity in ulcerative colitis. Dig Dis Sci 1982;27:533–537. Hodgson HJF, Bhatti M. Assessment of disease activity in ulcerative colitis and Crohn’s disease. Inflamm Bowel Dis 1995; 1:117–134. Lemann M, Galian A, Rutgeerts P, Van Heuverzwijn R, Cortot A, Viteau JM, Elewaut A, Belaiche J, Froguel E, Modigliani R. Comparison of budesonide and 5-ASA enemas in active distal ulcerative colitis. Aliment Pharmacol Ther 1995;9:557–562.
Received November 13, 1996. Accepted June 9, 1998. Address requests for reprints to: Stephen B. Hanauer, M.D., Section of Gastroenterology, Department of Medicine, University of Chicago Medical Center, 5841 South Maryland Avenue, MC4076, Chicago, Illinois 60637. Fax: (773) 834-7209. Supported by a research grant from Astra Draco AB, Lund, Sweden and Astra USA Inc., Westborough, Massachusetts. Presented in part at the 1995 annual meeting of the American Gastroenterological Association in San Diego, California, and published in abstract form (Gastroenterology 1995;108:A832). The physician investigators of the U.S. Budesonide Enema Study Group are as follows: Naurang M. Agrawal, Tulane University School of Medicine, New Orleans, LA; Sanjeev Arora, New England Medical Center–Tufts University, Boston, MA; Rambie Briggs, Center for Clinical Research, Tucson, AZ; Charles Elson, University of Alabama, Birmingham, AL; Shaban Faruqui, Baton Rouge, LA; Robert S. Fisher, Temple University, Philadelphia, PA; Lawrence S. Friedman, New York, NY; Oliver Gilliam, Heartland Research Center, South Bend, IN; Paul Goldberg, Halifax Clinical Research Center, Daytona Beach, FL; Stephen B. Hanauer, University of Chicago, Chicago, IL; Clifford G. Harman, Salt Lake Gastroenterology Clinic, Salt Lake City, UT; R. Bruce Johnson, Sharp-Reese-Stealy Medical Group, San Diego, CA; James V. Jones, Green Clinic, Ruston, LA; Seymour Katz, Great Neck, NY; Robert M. Kerr, Bowman-Gray School of Medicine, Winston-Salem, NC; George Koval, West Hills Gastroenterology, Portland, OR; Douglas Levine, University of Washington, Seattle, WA; Mark Mellow, Baptist Medical Center of Oklahoma, Oklahoma City, OK; William Murchison, Colorado Springs Medical Center, Colorado Springs, CO; Timothy Nostrant, University of Michigan, Ann Arbor, MI; C. Andrew Pickens, Clinical Research Associates, Spartanburg, SC; Ronald Pruitt, Nashville, TN; Malcolm Robinson, University of Oklahoma Health Sciences Center, Oklahoma City, OK; Seymour M. Sabesin, Rush Presbyterian–St. Luke’s Medical Center, Chicago, IL; Michael A. Safdi, Greater Cincinnati Gastroenterology Associates, Cincinnati, OH; Fergus Shanahan, UCLA Medical Center, Los Angeles, CA; Eapen Thomas, Mountain Home, TN; Arvydas Vanagunas, Chicago, IL; David T. Weinberg, Minnesota Clinical Study Center, Fridley, MN; Barry D. Winston, Houston, TX; Lawrence D. Wruble, Memphis Gastroenterology, Memphis, TN; and Sheldon Zinberg, Rico Rivera, CA.
ALIMENTARY TRACT Budesonide Enema for the Treatment of Active, Distal Ulcerative Colitis and Proctitis: A Dose-Ranging Study STEPHEN B. HANAUER,* MALCOLM ROBINSON,‡ RONALD PRUITT,§ AUDREY J. LAZENBY,\ TORE PERSSON,¶ LARS–GORAN NILSSON,¶ KAREN WALTON–BOWEN,# LLOYD P. HASKELL,# and JEFFREY G. LEVINE# for the U.S. BUDESONIDE ENEMA STUDY GROUP *Department of Medicine, University of Chicago, Chicago, Illinois; ‡Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; §Department of Medicine, Nashville Medical Research Institute, Nashville, Tennessee; \Department of Pathology, The Johns Hopkins University, Baltimore, Maryland; ¶Departments of Clinical Research and Development and Biostatistics and Data Processing, Astra Draco AB, Lund, Sweden; and #Departments of Biostatistics and Clinical Research, Astra USA Inc., Westborough, Massachusetts
Background & Aims: Budesonide is a highly potent topical glucocorticosteroid that is characterized by low systemic availability as a result of high first-pass hepatic metabolism. The aim of this study was to evaluate the efficacy and safety of three doses of an enema preparation of budesonide in patients with active distal ulcerative colitis/proctitis. Methods: In a double-blind multicenter trial, 233 patients were randomized to receive either a placebo enema or budesonide enema at a dose of 0.5 mg/100 mL, 2.0 mg/100 mL, or 8.0 mg/100 mL. The primary efficacy variables were an improvement of sigmoidoscopic inflammation grade, total histopathology score, and remission rates. Effects on cortisol concentrations were also assessed. Results: After 6 weeks of treatment, there was significant improvement in sigmoidoscopy and histopathology scores in the budesonide 2.0-mg and 8.0-mg dose groups compared with placebo. Remission was achieved in 19% of patients in the 2.0-mg budesonide group (P # 0.050) and 27% of patients in the 8.0-mg budesonide group (P # 0.001) compared with 4% in the placebo group. More than 90% of all budesonide patients had a normal adrenocorticotropin (ACTH)stimulated cortisol response at the last visit. The budesonide enemas were well tolerated. Conclusions: Budesonide enema is both effective and safe for the treatment of active distal ulcerative colitis/proctitis. A dose of 2.0 mg/100 mL budesonide is the lowest effective dose.
lcerative colitis is a chronic inflammatory bowel disorder of unknown origin that is characterized by short-term and long-term inflammation of the bowel. The proximal extent of the colonic mucosal inflammation varies among individuals, but almost always involves the rectum.1 Anti-inflammatory agents such as mesalamine and glucocorticosteroids administered orally or as an
U
enema are the most common forms of treatment.2,3 Enemas have the advantage of treating proctitis and left-sided disease locally because they may reach to (but seldom beyond) the splenic flexure. Unfortunately, conventional steroid enemas may have unwanted glucocorticosteroid side effects because of high systemic exposure.4 Budesonide is a glucocorticosteroid that is structurally related to 16a-hydroxyprednisolone. It has a high topical anti-inflammatory effect due to its high affinity for the glucocorticosteroid receptor and low systemic activity by virtue of its extensive first-pass hepatic metabolism (with resultant metabolites virtually devoid of significant glucocorticosteroid activity).4,5 Budesonide has been used in the treatment of asthma, allergic rhinitis, ulcerative colitis, and Crohn’s disease (in an oral formulation designed to be released in the ileum and proximal colon), with efficacy similar to that of conventional steroids but with few adverse events and significantly less impact on the hypothalamic-pituitary-adrenal axis.2,4,6–9 The suspension enema formulation of budesonide (Entocort enema; Astra Draco AB, Lund, Sweden) is designed to deliver the drug to the distal colon. Previous studies have shown it to be as effective as other steroid and mesalamine enemas.2,7–10 The present study was designed to assess the efficacy and safety of three doses of budesonide enema vs. placebo enema when administered once daily at bedtime for 6 weeks in the treatment of active distal ulcerative colitis.
Patients and Methods Patient Selection Eligible patients were outpatients older than 18 years with newly diagnosed or ongoing active, distal (to splenic r 1998 by the American Gastroenterological Association 0016-5085/98/$3.00
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flexure) ulcerative colitis extending from 5 to 50 cm from the anal ring. Patients were required to have a sigmoidoscopic inflammation grade score of 2 or greater at inclusion (see Study Design). Symptoms of active distal ulcerative colitis/proctitis were to include at least one of the following changes in bowel function: frequency and urgency of stools, presence of diarrhea, or presence of grossly visible blood. Significant exclusion criteria included (1) pregnant or nursing women; (2) presence of symptomatic, organic disease of the gastrointestinal tract (with the exception of rectal hemorrhoids or hiatal hernia); (3) presence of any significant laboratory abnormalities; (4) a history of active ulcerative colitis proximal to the splenic flexure; (5) hypersensitivity to glucocorticosteroids; and (6) ova or parasites, pathogens, and/or toxins (Clostridium difficile) found in stools. Topical steroids were not allowed within the previous 2 weeks before screening, and systemic steroids (orally or rectally administered) were not allowed within the preceding 4 weeks before screening. Any rectally administered drug for ulcerative colitis had to be discontinued 2 weeks before randomization. Patients were allowed to take oral mesalamine products as long as their dose had remained constant during the 2 months before randomization; this dose could not be changed during the study period. Initiation of treatment with an oral mesalamine product was not allowed during the week before screening or during the study. The study was approved by the institutional review board at each center or through a central review board and was conducted in accordance with the Declaration of Helsinki.
Study Medication Budesonide enema was manufactured by Astra Draco AB (Lund, Sweden) and consisted of dispersible tablets containing 0.58, 2.3, or 9.2 mg budesonide, which were then dissolved in 115 mL of 0.9% saline solution (the enema vehicle was manufactured by Astra Pharmaceutical Production, So¨derta¨lje, Sweden) by the patient just before use. Because the average residual volume in the enema bottle is 15 mL, the actual dose of budesonide administered was 0.5, 2.0, or 8.0 mg/100 mL. All tablets were identical in appearance. The reference drug was a placebo tablet that was identical in appearance to the budesonide tablets and dispersed in an identical enema vehicle.
Study Design The study was a 6-week randomized, double-blind, multicenter trial performed at 33 centers throughout the United States from July 1991 to January 1993. After a 1-week screening period, 233 patients were randomized to three treatment arms and one placebo arm. All patients were required to sign an informed consent. At randomization, patients were assigned to one of the following four study arms: placebo enema or 0.5, 2.0, or 8.0 mg/100 mL budesonide enema. All enemas were given once daily at bedtime. The patients were instructed to retain the enema for as long as possible, preferably over night. A complete medical history was taken, and a complete physical examination was performed during the screening
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period. A second complete physical examination was again performed at week 6. Stool samples were obtained during the screening period to detect pathogens and C. difficile toxin unless done within 1 month before screening flexible sigmoidoscopy. Flexible sigmoidoscopy was performed during the screening period and at weeks 2, 4, and 6. This was done to evaluate the extent of the inflammation (measured from the anal ring in centimeters), to obtain tissue for histopathology (biopsies were performed only during the screening flexible sigmoidoscopy and at the end of the study at week 6), and to assess the macroscopic appearance of the most severely inflamed area of mucosa (sigmoidoscopic inflammation grade). Sigmoidoscopic inflammation was graded on a 4-point scale as follows: 0, normal mucosa; 1, edema and/or loss of visible mucosal vascularity, granularity; 2, friability (defined as visible, induced bleeding on examination), petechiae; and 3, spontaneous hemorrhage, visible ulcers. Biopsy specimens for histology were obtained from a distance between 5 and 10 cm from the anal ring. Two samples were obtained from the same level at each sigmoidoscopy and labeled only with a code number. All biopsy specimens were evaluated by the same pathologist (A.J.L.), who was blind to the treatment allocation. Biopsy specimens were histologically graded for active inflammation, chronic inflammation, and crypt distortion (Table 1). This scale is similar to that developed by Truelove and Richards.11 The total histopathology score was derived from the sum of the above three components (active inflammation, chronic inflammation, and crypt distortion). A colonoscopy was performed at screening if the upper margin of the affected area could not be seen during flexible sigmoidoscopy. Colonoscopy performed within 1 month before screening could be used in lieu of a colonoscopy at screening if detailed information on the results were available. At each visit (screening, week 2, week 4, and week 6), the physician, with the assistance of patient diary cards (see below), assessed the patient for symptoms of colitis (diarrhea, abdominal pain, intermittent tenesmus, and rectal bleeding; the investigator assessment of ulcerative colitis symptom score). Global evaluation (investigator global evaluation) was also performed based on a 5-point scale as follows: 0, normal or in remission; 1, mild (symptoms present, but not bothersome); 2, moderate (symptoms bothersome); 3, severe (symptoms interfere with normal activities); and 4, incapacitating (symptoms do not allow patient to continue normal activities). Patients were also required to fill out daily diary cards and record their daily rating of quality of life (Global Quality of Life) using a 4-point scale (0, excellent; 1, good; 2, fair; and 3, poor), the number of formed stools with and without visible blood, and the number of episodes of diarrhea with and without blood. They also recorded symptoms of urgency, abdominal pain, and painful bowel evacuations on a 0 (none) to 4 (incapacitating) scale. Laboratory evaluations included hematology, blood chemistry, serum pregnancy test (females only), urinalysis (all done during screening and at week 6), and morning basal and
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Table 1. Histopathology Evaluation Inflammation grade Active inflammation
Score 0
1
2
3
Chronic inflammation
0
1
2
Crypt distortion
0
1
2
3
Intensity
Histological criteria
Normal
Neutrophils not present in crypt or surface epithelium and no exudate, erosion, or ulceration Low grade Neutrophils present transmigrating through the crypt epithelium or within crypt lumina in ,20% of crypts; no erosions or ulcers Moderate Neutrophilic infiltration in .20% of crypts or presence of erosions (loss of superficial mucosa accompanied by fibroinflammatory exudate) High grade Presence of ulcers (loss of the entire thickness of mucosa and recognized as fragments of inflamed gradation tissue) No increase Number of chronic inflammatory cells within normal limits and present primarily in the superficial lamina propria Moderate Mononuclear cells present in moderate numbers and aggregated between crypts at the base of the lamina propria Severe Marked increase in chronic inflammation shown by sheets of chronic cells None Crypts had normal outlines with only artifactual irregularities Mild Scattered or rare crypts showing irregular (bent, forked) outline Moderate Approximately 25%–50% of crypts with an irregular outline Severe More than 50% of crypts with an irregular outline
ACTH-stimulated cortisol concentrations (done at randomization before receiving study medication and at week 6). Basal and ACTH-stimulated cortisol blood samples were obtained just before and 1 hour after intramuscular injection of Cortrosyn, 0.25 µg (Organon, NJ). All analyses were performed at one central reference laboratory (SmithKline Beecham Clinical Laboratories). Adverse events were recorded at each visit. The likelihood of the relationship to blinded medication was rated as none,
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unlikely, possible, probable, or highly probable. Adverse events were also evaluated as possible glucocorticosteroid-associated side effects.
Statistical Analysis A sample size of 200 patients was based on the expected differences in change from baseline in sigmoidoscopic inflammation score compared with placebo. The standard deviation of change in sigmoidoscopy score was assumed to be 1, baseline score was 2 or 3, and hypothesis testing was to be completed using two-tailed tests at the 0.050 level of significance. With 50 patients per treatment group, the power was 80% if the true difference between two treatments was 0.58. For each efficacy variable, the analysis started with an overall comparison by analysis of variance or x2 test. When this was significant the groups were compared pairwise. All P values for paired comparisons were for the two-sided Student’s t test or the equivalent x2 without correction for multiplicity. The primary efficacy variables included the mean change from baseline for the sigmoidoscopic inflammation grade, total histopathology score (sum of all three components), and remission rate. The primary definition of remission was rigorously defined as three or less bowel movements per day; no blood in stools; no symptoms of urgency, abdominal pain, or painful evacuations; and a sigmoidoscopic inflammation grade score of 0. Patients had to achieve all of these criteria for the 2 days preceding the visit to be considered in remission. In addition, there were two secondary definitions of remission that included sigmoidoscopic inflammation grade score of 0 and investigator global evaluation score of 0 or a decrease of 2 or more points from baseline. Secondary efficacy variables included changes in the investigator assessment of active ulcerative colitis symptoms, investigator global evaluation, global quality of life, and improvement in the extent of the lesion (in centimeters). Safety variables included changes in basal plasma and ACTH-stimulated cortisol concentrations from baseline and the percent of patients with normal basal cortisol values; normal response to ACTH stimulation; and the percentage of patients who had both normal basal and normal ACTHstimulated plasma cortisol response. Normal basal cortisol was defined as $150 nmol/L. Normal ACTH-stimulated cortisol response was defined as a poststimulated cortisol value $400 nmol/L and/or an increase of $200 nmol/L. The incidence of reported adverse events was also considered. Two approaches to analysis were used: intent-to-treat and per protocol analyses. The intent-to-treat population included all patients who received double-blind medication, had baseline data, and had double-blind observation for at least one visit. Because there were no significant differences between these analyses, only the intent-to-treat analysis is presented. To determine changes from the baseline, the on therapy data was subtracted from the baseline data. Thus, the larger the positive number, the greater the change from baseline and the greater the improvement. Mean changes from baseline for both primary and secondary variables were analyzed using analysis of
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variance techniques that included baseline, center, and treatment as factors in the model. Remission rates and percent of patients with normal cortisol values were analyzed using categorical data techniques. For missing values, the ‘‘last value carried forward’’ procedure was used from the first follow-up visit (week 2). Although week 6 was the primary end point, information for week 2 and week 4 is also included where applicable.
Results Patients A total of 233 patients were randomized (33 patients who were in the screening phase at the time recruitment ended were randomized), with 60 to the placebo group, 57 to the 0.5 mg/100 mL budesonide group, 56 to the 2.0 mg/100 mL budesonide group, and 60 to the 8.0 mg/100 mL budesonide group. Table 2 shows the patient demographic data, number of patients using products containing mesalamine, and baseline data for the primary and secondary efficacy criteria. There Table 2. Baseline Data Budesonide dose Placebo Patient characteristics No. of patients Age (yr) #40 .40 Mean Sex Male Female Race White Black Hispanic Other SIG Grade 2 Grade 3 No. of patients using mesalamine products Mean baseline scores Sigmoidoscopic inflammation grade Total histopathology Investigator assessment of ulcerative colitis symptoms Investigator global evaluation Patient global quality of life Extent of lesion (cm)
0.5 mg
2.0 mg
8.0 mg
60
57
56
60
35 25 43
34 23 39
30 26 42
38 22 40
30 30
32 25
28 28
36 24
54 3 3 0
53 2 1 1
46 6 3 1
54 3 2 1
36 21
25 30
22 32
37 23
22
19
29
20
2.37 5.55
2.54 4.67
2.59 5.36
2.38 5.56
5.69
5.54
5.87
5.85
2.06
1.95
1.95
1.93
1.74 30.80
1.60 27.10
1.45 27.80
1.58 26.40
SIG, sigmoidoscopic inflammation grade.
were no important differences between groups. Table 3 shows the details of the patient discontinuations. There were more discontinuations from the placebo and budesonide 0.5-mg dose groups than from the budesonide 2.0-mg and 8.0-mg dose groups. Primary Efficacy End Points The sigmoidoscopic inflammation grade significantly improved in the 2.0-mg and 8.0-mg dose groups at week 6 (P # 0.001) compared with placebo. The 0.5-mg dose was not significantly different from placebo. Significance for the 2.0-mg group was reached at week 4 (P # 0.010), and significance for the 8.0-mg dose was reached at weeks 2 and 4 (P # 0.001) compared with placebo (Figure 1). Total histopathology score improved significantly at week 6 for the 2.0-mg group (P # 0.050) and for the 8.0-mg group (P # 0.001) compared with placebo. The 0.5-mg dose was not significantly different from placebo (Figure 2). Remission rates (as defined by the primary definition) were significant for the 2.0-mg dose at week 6 (P # 0.050) with 19% of patients in remission and for the 8.0-mg dose at week 6 (P # 0.001) with 27% of patients in remission, compared with placebo with 4% of patients in remission. Again, the 0.5-mg dose (7% of patients in remission) was not significantly different from placebo (Figure 3). There was no significant difference between the 2.0-mg and the 8.0-mg doses for any of the primary efficacy variables at any evaluated time point. Secondary Efficacy End Points Investigator assessment of ulcerative colitis symptoms was derived from the sum of four criteria. The mean change from baseline was significant for the 2.0-mg and 8.0-mg dose groups for each individual criteria as well as the total symptom score (Figure 4). The investigator’s global evaluation score, patient’s global quality of life score, and extent of the lesion all improved significantly by week 6 for the 2.0-mg and 8.0-mg dose groups (Table 4). There were also two secondary definitions of remission. For sigmoidoscopic inflammation grade score of 0, 15.7% of patients in the placebo group, 19.6% of patients in the 0.5-mg group (not statistically significantly different than placebo), 35.2% of patients in the 2.0-mg group (P # 0.010 vs. placebo), and 44.3% of patients in the 8.0-mg group (P # 0.001 vs. placebo) were in remission at week 6. When remission was defined as an investigator global evaluation grade of 0 or a decrease of 2 or more points from baseline, 41.5% of patients in the 2.0-mg group (P # 0.050) and 55.2% of patients in the 8.0-mg group (P # 0.001) were in
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Table 3. Patient Discontinuations Budesonide dose Reason for discontinuation
Placebo (n 5 60)
0.5 mg (n 5 57)
2.0 mg (n 5 56)
8.0 mg (n 5 60)
Total (n 5 233)
Inadequate response Protocol violations Adverse experiences Unsatisfactory compliance Withdrew consent Lost to follow-up Total discontinued
17 (28) 2 (3) 3 (5) 1 (2) 1 (2) 0 (0) 24 (40)
12 (21) 1 (2) 0 (0) 2 (4) 0 (0) 1 (2) 16 (28)
3 (5) 2 (4) 2 (4) 2 (4) 0 (0) 2 (4) 11 (20)
9 (15) 1 (2) 0 (0) 0 (0) 2 (3) 0 (0) 12 (20)
41 (18) 6 (2) 5 (2) 5 (2) 3 (1) 3 (1) 63 (27)
NOTE. Number (%) of patients discontinued from the trial.
remission compared with 20.0% of patients in the placebo group at week 6. Thirty-three percent (33.2%) of the patients in the 0.5-mg group were in remission at week 6, which was not statistically different from placebo. Cortisol and Safety Ninety-four percent of patients in the 0.5-mg group (not significant), 87% of patients in the 2.0-mg group (P # 0.050), and 64% of patients in the 8.0-mg group (P # 0.001) had normal basal cortisol values compared with 98% of patients in the placebo group at week 6. Ninety-six percent of patients in the 0.5-mg dose group (not significant), 91% of patients in the 2.0-mg dose group (P # 0.050), and 92% of patients in the 8.0-mg dose group (P # 0.050) had a normal ACTHstimulated cortisol response compared with 100% of patients in the placebo group at week 6. Ninety-one percent of patients in the 0.5-mg dose group (not significant), 78% of patients in the 2.0-mg dose group (P # 0.010), and 59% of patients in the 8.0-mg dose
Figure 1. Sigmoidoscopic inflammation grade. The adjusted mean changes from baseline show the improvement in inflammation grade for each treatment arm at each evaluated time point. Budesonide enema at 2.0 mg significantly improved sigmoidoscopic inflammation after 4 weeks (**P # 0.010 vs. placebo) and 6 weeks (***P # 0.001 vs. placebo). Budesonide enema at 8.0 mg significantly improved sigmoidoscopic inflammation after 2, 4, and 6 weeks (***P # 0.001 vs. placebo).
group (P # 0.001) had both normal basal cortisol values and normal ACTH-stimulated cortisol response compared with 98% of patients in the placebo group at week 6. When the mean changes in basal values from baseline were compared, there was no statistically significant difference between the placebo and the 0.5-mg and 2.0-mg dose groups, whereas there was a statistically significant difference between placebo and the 8.0-mg dose group (P # 0.001). Both the 2.0-mg and 8.0-mg dose groups had a statistically significant larger mean change from baseline ACTH-stimulated cortisol values compared with placebo (P # 0.001) at week 6. The 0.5-mg dose group was not different from placebo for the ACTH-stimulated cortisol values (Table 4). No clinically relevant possible glucocorticosteroid side effects were reported. The proportion of patients with one or more adverse events was not statistically significantly different between the groups for all events regardless of relationship to study drug (none, unlikely, possible, probable, or highly probable). The number and percent of adverse events that were reported as possibly related to study drug (unlikely, possible, probable, or highly probable)
Figure 2. Total histopathology score at week 6. Mean change from baseline showing the improvement in total histopathology score (the sum of the active and chronic inflammation and crypt distortion components). Budesonide enema at 2.0 and 8.0 mg significantly improved total histopathology scores after 6 weeks of treatment (*P # 0.050 vs. placebo and ***P # 0.001 vs. placebo, respectively).
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Cushing’s syndrome. For all adverse events regardless of relationship and for adverse events related to study medication, the most frequently reported adverse events were headache, back pain, dyspepsia, and nausea. There was one death during this study that resulted from an acute myocardial infarction in a patient on placebo enema.
Discussion
Figure 3. Percent of patients in remission (primary definition). After 6 weeks of treatment, both budesonide enema at 2.0 mg and 8.0 mg induced remission in a higher percentage of patients compared with placebo (*P # 0.050 and ***P # 0.001, respectively). For week 6, 95% confidence intervals are shown in parentheses. Remission was defined as including all of the following during the 2 days before physician visit: three or less bowel movements per day; no blood in stool; no symptoms of urgency, abdominal pain, or painful evacuations; and sigmoidoscopic inflammation grade of 0.
were also not different between study groups: 18 patients (30%) in the placebo group, 21 patients (37%) in the 0.5-mg budesonide group, 20 patients (36%) in the 2.0-mg group, and 24 patients (40%) in the 8.0-mg group experienced drug-related adverse events. Serious adverse events were few with 4 patients (6.7%) in the placebo group and 3 patients (1.7%) in the budesonide groups (all budesonide groups combined). One (1.7%) patient in the budesonide 8.0-mg group had an event that was reported as adrenal insufficiency. Four patients (3.3%) in the placebo group and 2 (3.3%) in the 8.0-mg budesonide group had an event that was reported as
Figure 4. Total investigator assessment of ulcerative colitis symptom score. Mean change from baseline showing improvement in the sum of the ulcerative colitis symptom score (sum of diarrhea, abdominal pain, intermittent tenesmus, and rectal bleeding). Budesonide enema at 0.5 mg significantly improved ulcerative colitis symptom scores at week 2 and week 6 (*P # 0.050) compared with placebo. Budesonide enema at 2.0 mg and 8.0 mg significantly improved colitis symptom scores at week 2 (**P # 0.010 and ***P # 0.001, respectively) and week 4 and week 6 (***P # 0.001) compared with placebo.
Rectally administered steroids for distal ulcerative colitis/proctitis have been used extensively for more than 30 years. Unfortunately, high systemic availability of conventional steroids has the disadvantage of affecting the hypothalamic-pituitary-adrenal axis and inducing glucocorticosteroid side effects. Prolonged use of these enemas may be accompanied by these undesirable effects.8,12 Budesonide is in a new class of glucocorticosteroids that have a high topical effect as well as a high first-pass hepatic metabolism with low systemic availability.4 Budesonide enema reaches its maximum spread in approximately 15 minutes.13 The drug is nearly 100% absorbed into the portal circulation within 3–4 hours of administration.5 Approximately 85% of budesonide undergoes first-pass metabolism in the liver with a resulting systemic availability of about 15%.5 This dose-ranging study showed dose-related efficacy of budesonide enema compared with placebo, which is in agreement with observations of an earlier dose-ranging study.9 Budesonide (0.5 mg/100 mL) was not significantly different from placebo for any of the primary variables and many of the secondary variables. In contrast, 2.0 mg/100 mL budesonide and 8.0 mg/100 mL budesonide were consistently superior to placebo for all the primary and secondary efficacy variables. Efficacy was seen as early as 2 weeks after initiation of treatment with continued improvement noted throughout the 6 weeks. For the primary efficacy variables, the 2.0-mg dose was not statistically significantly different from the 8.0-mg dose; however, it should be noted that this study was not designed to detect a difference between these active groups. The low primary remission rate in this study may be explained by the rigorous criteria the patient had to meet to be considered in remission. This resulted in remission rates of 4%, 7%, 19%, and 26% for placebo and 0.5 mg, 2.0 mg, and 8.0 mg budesonide, respectively. This stringent definition produced remission rates that are lower than that usually seen with placebo, which is about 30%.14 With the less strict secondary remission criteria, remission rates were closer to expected ones. In a similarly designed study comparing 2 mg/100 mL budesonide enema to placebo and Cortenema (Solvay Pharmaceuticals, Marietta, GA), the same strict criteria for primary
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Table 4. Investigator Assessment, Secondary Efficacy Variables, and Cortisol Data Budesonide dose
Criteria Investigator assessment of ulcerative colitis symptoms Diarrhea Abdominal pain Intermittent tenesmus Rectal bleeding Total (sum of all four) Secondary efficacy variables at week 6 Investigator global evaluation score Global quality of life score Extent of lesion (cm) Cortisol data Baseline cortisol (nmol/L) Basal ACTH-stimulated Week 6 cortisol (nmol/L) Basal ACTH-stimulated Percent with normal cortisol at week 6 d Basal ACTH-stimulated Both
Placebo (n 5 59)
0.5 mg (n 5 57)
2.0 mg (n 5 55)
8.0 mg (n 5 60)
0.08 0.17 0.13 0.23 0.60
0.42 a 0.35 0.61 b 0.39 1.76 a
0.55 b 0.62 b 0.62 b 0.84 c 2.63 c
0.53 b 0.46 a 0.70 c 0.87 c 2.59 c
0.28 0.04 4.40
0.68 a 0.39 a 5.80
0.88 c 0.53 b 11.00 a
1.10 c 0.57 c 13.90 c
407 729
415 721
382 683
369 698
385 739
393 702
322 583 c
246 c 529 c
98 (94–100) 100 (99–100) 98 (94–100)
94 (86–100) 96 (90–100) 91 (83–99)
87 a (78–97) 91 a (83–99) 78 b (66–90)
64 c (51–77) 92 a (85–100) 59 c (45–73)
NOTE. Individual and total adjusted mean change from baseline scores at week 6 for the investigator assessment of symptoms. The adjusted mean change from baseline for the improvement in the remainder of the secondary efficacy variables. Mean basal and ACTH-stimulated cortisol data at baseline and at week 6 are shown. The percentage of patients with normal values for basal cortisol, ACTH-stimulated cortisol response, and the percentage of patients who had both normal basal cortisol and normal ACTH-stimulated cortisol responses are shown at week 6. aP # 0.050 vs. placebo. bP # 0.010 vs. placebo. cP # 0.001 vs. placebo. d95% confidence intervals are shown in parentheses.
remission was used.15 In that study, the percentage of patients achieving remission was 16% for budesonide enema, 11% for Cortenema, and 10% for placebo. Although the results did not reach statistical significance, the low remission rates are consistent with the present study. The fact that histopathology scores in the present study improved significantly is also of importance because biopsy healing tends to lag behind macroscopic healing.16 It has also been suggested that symptoms may correlate more with macroscopic findings than histopathology findings17; however, even sigmoidoscopic improvement may lag behind symptomatic improvement.18 Thus the significant improvement of all of these criteria (histopathology, sigmoidoscopic inflammation, and symptoms) in this study is further evidence of the efficacy of budesonide enema. A dose-related effect on basal cortisol and ACTHstimulated cortisol values was also found. Budesonide at 0.5 mg/100 mL had no significant effect on the hypothalamic-pituitary-adrenal axis compared with placebo. Budesonide at 8.0 mg/100 mL had the greatest effect on the hypothalamic-pituitary-adrenal axis with little improved efficacy over the 2.0-mg dose. During the 6-week study, the dose-related reduction of basal cortisol and
ACTH-stimulated cortisol values were not associated with any clinically significant glucocorticosteroid side effects. More than 90% of patients treated with budesonide enema (any dose) had a normal ACTH-stimulated cortisol response at week 6, indicating that adrenal function was not severely adversely affected by budesonide enema in doses up to 8.0 mg/100 mL. Other studies comparing prednisolone enema with budesonide enema have shown an even lesser effect of budesonide enema on the hypothalamic-pituitary-adrenal axis. In these studies, a significant effect by prednisolone, but not by budesonide, was seen.2,8,9 In one of these studies,2 the treatment period was 8 weeks with patient evaluations at 2, 4, and 8 weeks. Clinical remission was seen as early as 4 weeks and doubled by 8 weeks (both the budesonide and prednisolone groups), but with a significantly larger plasma cortisol suppression effect in the prednisolone group.2 Thus the apparent lack of adrenal suppression, even when used for a prolonged time of 8 weeks, would seem to be important. Budesonide enema at a dose of 2.0 mg/100 mL has also been compared with a 4-g mesalamine enema10 and a 1-g mesalamine enema19 with similar efficacy and adverse event profiles.
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Budesonide enema was well tolerated and safe. The number of patients experiencing adverse events (including serious adverse events) and the type and frequency of adverse events were similar for all doses of budesonide enema and placebo enema. The number of patients discontinuing the study was highest in the placebo and the 0.5 mg/100 mL budesonide groups and was mostly a result of inadequate response. In conclusion, budesonide enemas at 2.0 and 8.0 mg/100 mL were both clinically and statistically significantly superior to placebo in the treatment of active distal ulcerative colitis/proctitis. Budesonide enema had little effect on the hypothalamic-pituitary-adrenal axis and was safe and well tolerated. On the basis of this information, it seems that 2.0 mg/100 mL budesonide is the optimal dose for efficacy in association with little effect on the hypothalamic-pituitary-adrenal axis.
References 1. Kirsner JB. The historical basis of the idiopathic inflammatory bowel diseases. Inflamm Bowel Dis 1995;1:2–26. 2. Lo¨fberg R, Thomsen O, Langholz E, Schio¨ler R, Danielsson Å, Suhr O, Graffner H, Påhlman L, Matzen P, Mo¨ller-Petersen JF, Halvorsen L, Hovdenak N, Willen R, Persson T, Seidegård C. Budesonide versus prednisolone retention enemas in active distal ulcerative colitis. Aliment Pharmacol Ther 1994;8:623–629. 3. Sutherland LR, Martin F, Greer S, Robinson M, Greenberger N, Saibil F, Martin T, Sparr J, Prokipchuk E, Borgen L. 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis proctosigmoiditis, and proctitis. Gastroenterology 1987;92:1894– 1898. 4. Rutgeerts P. Budesonide enemas for topical therapy of ulcerative colitis. Can J Gastroenterol 1990;4:415–416. 5. Dahlstrom K, Edsbacker S, Kallen A. Rectal pharmacokinetics of budesonide. Eur J Clin Pharmacol 1996;49:293–298. 6. Greenberg GR, Feagan BG, Martin F, Sutherland L, Thomson A, Williams C, Nilsson L-G, Persson T. Oral budesonide for active Crohn’s disease. N Engl J Med 1994;331:836–841. 7. Porro GB, Prantera C, Campieri M, Petrillo M, Campanini MC, Gionchetti P, Grandinetti G, Mangiarotti R, Brunetti G, Ranzi T. Comparative trial of methylprednisolone and budesonide enemas in active distal ulcerative colitis. J Gastroenterol Hepatol 1994;6: 125–130. 8. Thomsen O, Andersen T, Langholz E, Lo¨fberg R, Malchow-Mo¨ller A, Matzen P, Nordstro¨m H, Persson T. Lack of adrenal gland suppression with budesonide enema in active distal ulcerative colitis: a prednisolone-controlled 8-week study. Eur J Gastroenterol Hepatol 1994;6:507–511. 9. The Danish Budesonide Study Group. Budesonide enema in distal ulcerative colitis: a randomized dose-response trial with prednisolone enema as positive control. J Gastroenterol 1991;26:1225– 1230. 10. Lamers C, Meijer J, Engels L, Van Heuverzwijn R, Cortot A, Viteau JM, Elewaut A, Belaiche J, Froguel E, Modigliani R. Comparative study of the topically acting glucocorticosteroid budesonide and a 5-ASA enema for proctitis and proctosigmoiditis (abstr). Gastroenterology 1991;100:A223. 11. Truelove SC, Richards WCD. Biopsy studies in ulcerative colitis. BMJ 1956;1:1315–1318. 12. Lee DAH, Taylor GM, James VHT, Walker G. Plasma prednisolone levels and adrenocortical responsiveness after administration of
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Received November 13, 1996. Accepted June 9, 1998. Address requests for reprints to: Stephen B. Hanauer, M.D., Section of Gastroenterology, Department of Medicine, University of Chicago Medical Center, 5841 South Maryland Avenue, MC4076, Chicago, Illinois 60637. Fax: (773) 834-7209. Supported by a research grant from Astra Draco AB, Lund, Sweden and Astra USA Inc., Westborough, Massachusetts. Presented in part at the 1995 annual meeting of the American Gastroenterological Association in San Diego, California, and published in abstract form (Gastroenterology 1995;108:A832). The physician investigators of the U.S. Budesonide Enema Study Group are as follows: Naurang M. Agrawal, Tulane University School of Medicine, New Orleans, LA; Sanjeev Arora, New England Medical Center–Tufts University, Boston, MA; Rambie Briggs, Center for Clinical Research, Tucson, AZ; Charles Elson, University of Alabama, Birmingham, AL; Shaban Faruqui, Baton Rouge, LA; Robert S. Fisher, Temple University, Philadelphia, PA; Lawrence S. Friedman, New York, NY; Oliver Gilliam, Heartland Research Center, South Bend, IN; Paul Goldberg, Halifax Clinical Research Center, Daytona Beach, FL; Stephen B. Hanauer, University of Chicago, Chicago, IL; Clifford G. Harman, Salt Lake Gastroenterology Clinic, Salt Lake City, UT; R. Bruce Johnson, Sharp-Reese-Stealy Medical Group, San Diego, CA; James V. Jones, Green Clinic, Ruston, LA; Seymour Katz, Great Neck, NY; Robert M. Kerr, Bowman-Gray School of Medicine, Winston-Salem, NC; George Koval, West Hills Gastroenterology, Portland, OR; Douglas Levine, University of Washington, Seattle, WA; Mark Mellow, Baptist Medical Center of Oklahoma, Oklahoma City, OK; William Murchison, Colorado Springs Medical Center, Colorado Springs, CO; Timothy Nostrant, University of Michigan, Ann Arbor, MI; C. Andrew Pickens, Clinical Research Associates, Spartanburg, SC; Ronald Pruitt, Nashville, TN; Malcolm Robinson, University of Oklahoma Health Sciences Center, Oklahoma City, OK; Seymour M. Sabesin, Rush Presbyterian–St. Luke’s Medical Center, Chicago, IL; Michael A. Safdi, Greater Cincinnati Gastroenterology Associates, Cincinnati, OH; Fergus Shanahan, UCLA Medical Center, Los Angeles, CA; Eapen Thomas, Mountain Home, TN; Arvydas Vanagunas, Chicago, IL; David T. Weinberg, Minnesota Clinical Study Center, Fridley, MN; Barry D. Winston, Houston, TX; Lawrence D. Wruble, Memphis Gastroenterology, Memphis, TN; and Sheldon Zinberg, Rico Rivera, CA.