OBJECTIVES:

To evaluate the efficacy and safety of oral budesonide for maintenance of remission in patients with mild to moderately active Crohn's disease (CD) of the ileum and/or ascending colon.

METHODS:

Four double-blind, placebo-controlled trials with identical protocols were combined according to a predetermined analysis plan. Three hundred eighty patients with CD in medically induced remission (CD activity index [CDAI]150) were randomized to receive oral budesonide 3 mg, 6 mg, or placebo daily for 12 months. The primary outcome measure was time to relapse (increase in CDAI of 60 points above baseline and >150).

RESULTS:

The median time to relapse was 268, 170, and 154 days for budesonide 6 mg, budesonide 3 mg, and placebo groups, respectively (p= 0.0072). The frequency of adverse events and glucocorticosteroid side effects were similar in all groups.

CONCLUSION:

Budesonide 6 mg/day is effective for prolonging time to relapse and for significantly reducing rates of relapse at 3 and 6 months but not 12 months in patients with CD in medically induced remission.

INTRODUCTION

The hallmark of Crohn's disease (CD) is a chronic relapsing course (^1,2). Patients alternate between acute symptomatic relapses and spontaneous or drug-induced remissions (^1,2). The primary goals of treatment are to induce remission and then maintain clinical improvement or remission, resulting in a reduction or resolution of signs and symptoms (³).

Systemic corticosteroids administered at high doses (prednisone 0.75 mg/kg/day and prednisolone 1.0 mg/kg/day) are effective for induction of remission in patients with mildly to moderately active CD (^4,5) but frequently result in steroid-related adverse events (⁶). In contrast, maintenance of remission studies with low-dose systemic corticosteroids (prednisone 0.25 mg/kg/day and prednisolone 8 mg/day) failed to demonstrate efficacy (^4,5). Because of the potential for adverse events, high-dose systemic corticosteroids have not been evaluated as a maintenance therapy.

The nonsystemic corticosteroid (budesonide) is also effective for induction of remission in patients with mildly to moderately active CD (^7,8,9) and has a lower frequency of steroid-related adverse events than prednisolone (^10,11). Patients from 4 budesonide induction trials (^7,9,10,11) who entered remission were rerandomized into 4 placebo-controlled maintenance trials of similar design that evaluated the efficacy of oral budesonide capsules 3 or 6 mg. Two out of the 4 of these small maintenance studies demonstrated that budesonide 6 mg/day prolonged the time to relapse of CD, but all 4 studies failed to show a difference in the proportion of patients who remained in remission at 1 yr (^12,13,14,15).

Because the sample size of each of the 4 budesonide maintenance trials was determined by the actual remission rates achieved during the 4 individual induction-of-remission trials that preceded the 4 maintenance trials, rather than by an estimate of the remission rates for budesonide required to demonstrate a significant maintenance effect, it was not anticipated that the 4 small maintenance trials would independently have power to detect a clinically meaningful maintenance benefit. A predetermined analysis was, therefore, planned in which the results of all 4 maintenance studies would be combined using patient level data. We now present the results of this combined analysis of 4 trials in which patients with CD in medically induced remission (following induction therapy with budesonide, prednisolone, or placebo) received oral budesonide capsules 3 mg, 6 mg, or placebo daily for 52 wk.

MATERIALS AND METHODS

Patient Selection

The four studies were performed between April 1991 and August 1998. Eligible patients were men and women at least 18 yr of age with a confirmed diagnosis of CD involving the ileum and/or ascending colon and a previous relapse with mildly to moderately active disease (defined as a CD activity index [CDAI] score between 200 and 450 inclusive) successfully treated (in clinical remission with CDAI score 150) within 10–12 wk with either oral budesonide 3, 9g, or 15 mg daily, a tapering course of prednisolone or placebo. For those patients treated with a tapering course of prednisolone, the following tapering schedule was used: 40 mg (weeks 1–2); 30 mg (weeks 3–4); 25 mg (week 5); 20 mg (week 6); 15 mg (week 7); 10 mg (week 8); 5 mg (weeks 9–10); and 2 mg (weeks 11–12); further dose titration was allowed to the level of no glucocorticosteroid intake, as judged by the investigator.

The following patients were not eligible: pregnant or lactating women; those who were allergic to budesonide or other corticosteroids; those with septic complication, abscess, local complication, active fistula (with the exception of chronic nondraining asymptomatic anorectal fistula), obstruction, stricture with proximal dilation confirmed by colonoscopy or small bowel x-ray within 180 days of entry into preceding induction of remission study; those with a known history of left-sided or rectal CD (except for scattered aphthous ulcers) confirmed by colonoscopy within 180 days of entry into the preceding induction of remission study; those with local or systemic infection (including septic lesions in the perianal region); those with active peptic ulcer disease; those with diabetes; those with clinically significant hepatic, renal, respiratory, musculoskeletal, cardiovascular, endocrine, neurologic, psychiatric, or other significant diseases; those who were alcohol or drug abusers; those receiving H₂-blockers or proton pump inhibitors; those receiving parenteral, enteral, or polymeric nutrition; those with another disease that contraindicated corticosteroids; those that were taking any corticosteroids during the course of the study; those with a planned in-patient hospitalization during the study; those with a history of carcinoma (excluding basal and squamous cell carcinoma) within 5 yr of entry into the preceding induction of remission study; those with enteric pathogens, Clostridium difficile toxin, ova, or parasites during screening for the preceding induction of remission study; those with ileostomy or colostomy; those with previous gastric surgery except for closure of perforation or selective vagotomy; those with resection of the ileum totaling more than 100 cm or any resection distal to the midtransverse colon; those with histologically documented gastrointestinal (GI) carcinoma or dysplasia within 5 yr of entry into the preceding induction of remission study; and those with recent (within 3 months) exposure to live viruses (including immunizations) such as chickenpox, measles, or polio, or to tuberculosis.

Concomitant Medications

Patients receiving loperamide and other opiates were eligible. Patients treated with other drugs for CD including metronidazole, tinidazole, sulfasalazine, mesalamine formulations, and 4-aminosalicylate were not eligible. Similarly, patients treated with any immunosuppressive agent including azathioprine, 6-mercaptopurine, methotrexate, cyclosporine A, and tacrolimus within 90 days were not eligible. Patients who had received glucocorticosteroids (oral, parenteral, inhaled, rectal, nasal, and topical) within 14 days were not eligible. Patients treated with cholestyramine were not eligible. Patients who had received another investigational drug within 30 days were not eligible.

Study Medication

Patients received 3 or 6 mg budesonide capsules or placebo capsules once daily before breakfast. The capsules were administered before breakfast. A double-dummy technique was utilized to conceal the treatment assignment. Two capsules were administered in 1 of 3 combinations: 2 placebo capsules; 1 placebo capsule and 1 budesonide 3 mg capsule; or 2 budesonide 3 mg capsules. The placebo capsules were identical in appearance (size, color, and shape) to the budesonide capsules.

Study Design

All 4 of the 52-wk studies were randomized, double-blind, placebo-controlled maintenance of remission trials, with similar study designs performed at a total of 95 centers in Australia, Belgium, Canada, Denmark, Germany, Ireland, Italy, the Netherlands, Sweden, the United Kingdom, and the United States (Table 1) (^12,13,14,15). Patients entering the maintenance studies were in remission, defined as a CDAI 150, and had previously been treated with budesonide, prednisolone, or placebo during the active phase of CD (CDAI 200) during a preceding induction of remission study. The first visit of the maintenance studies coincided with the final visit of the induction studies. Eligible patients were randomized to budesonide 6 mg, budesonide 3 mg, or placebo in a l:1:1 ratio (3 studies), or they were randomized to budesonide 6 mg or placebo in a 1:1 ratio (1 study). The randomization schedules for each of the 4 studies were generated with a computer by an unblinded statistician at AstraZeneca (Lund, Sweden).

Table 1. - One-Year Double-Blind, Placebo-Controlled, Maintenance of Remission Studies.

Full table

At entry, each patient's demographic characteristics, medical history, and current medications were recorded. Disease activity was assessed at the baseline (randomization) visit and after 3, 6, 9, and 12 months. Patients recorded on diary cards the frequency of loose stools, the extent of their abdominal pain, and their general well-being during the 7 days before each visit. At each visit, a physical examination, quality-of-life assessment, and laboratory tests were conducted and patients were asked whether any adverse events had occurred.

Clinical disease activity was assessed with the CDAI that was the primary efficacy measurement. CDAI scores 150 points indicate clinical remission, scores of 151–219 indicate mildly active disease, scores of 220–450 indicate moderately active disease, and scores >450 indicate severely active disease (^16,17). Disease-specific health-related quality of life was assessed with a secondary efficacy measurement, the self-administered Inflammatory Bowel Disease Questionnaire (IBDQ). The IBDQ is a previously validated instrument with four parts (bowel function, emotional status, systemic symptoms, and social function); scores <170 points indicate clinically active disease and scores 170 points indicate clinically inactive disease (¹⁸). The IBDQ was only used in studies 1 and 4.

Blood samples were taken for hematological and biochemical assessments, and for measurement of plasma cortisol and C-reactive protein (CRP; measured in 3 of the studies). ACTH stimulation tests were performed at 3 months in all 4 studies, and again at 12 months in 1 of the studies.

All adverse events were recorded and graded according to the World Health Organization Adverse Reaction Terminology criteria. At each clinic visit, patients were also specifically evaluated by the investigators for any possible glucocorticosteroid-associated adverse events using a checklist that included the following signs or symptoms: moon face, buffalo hump, acne, hirsutism, skin striae, easy bruising, swelling of ankles, mood swings, depression, insomnia, hair loss, and others. Adrenal cortisol production was assessed by evaluation of basal plasma cortisol levels and ACTH-stimulated plasma cortisol responses. ACTH tests were considered normal if basal plasma cortisol levels were in the normal range for the laboratory performing the analysis, and if the plasma cortisol 30 or 60 min after ACTH stimulation was within the expected poststimulation range for the laboratory performing the analysis and/or if the rise in plasma cortisol 30 or 60 min after ACTH stimulation was within the expected poststimulation rise range for the laboratory performing the analysis (normal rise).

Outcomes and Statistical Analysis

The intention-to-treat population included all patients who were randomized and received at least one dose of the study medication. The primary efficacy measure was the time to relapse. A relapse was defined as an increase in CDAI by at least 60 points from baseline to a value above 150, or withdrawal from the study due to worsening disease activity in the judgment of the investigator or the patient. The major secondary efficacy outcomes were time to relapse or discontinuation and the time to withdrawal. The other secondary efficacy variables were the proportion of patients with a relapse and the CDAI and IBDQ scores and the CRP concentrations at 3, 6, 9, and 12 months. The safety endpoints were: 1) adverse events; 2) glucocorticosteroid-associated adverse events; and 3) the laboratory data.

The time to relapse, time to relapse or discontinuation, and time in study were analyzed with respect to treatment using a generalized Wilcoxon test and Kaplan-Meier estimates and with respect to treatment and various prognostic factors using Cox regression models. The following independent prognostic variables were included in the regression models: treatment (placebo, budesonide 3 mg, budesonide 6 mg); CDAI score at entry into the preceding induction of remission study; CDAI score at entry into the maintenance study; study number (study number 1, 2, 3, or 4); treatment with prednisone in the preceding induction of remission study (no or yes); treatment with budesonide in the preceding induction of remission study (0, 3, 9, and 15 mg); gender (male or female); age; disease location (only ileal, colonic involvement); previous resection (no or yes); morning plasma cortisol at entry into the maintenance study; adrenal function at 3 months (normal or abnormal); disease duration; arthralgia/arthritis at entry into the preceding induction of remission study; CRP concentration >10 mg/l at entry into the preceding induction of remission study; and CRP concentration >10 mg/l at entry into the maintenance of remission study.

The proportion of patients with a relapse, mean CDAI and IBDQ scores, and CRP concentrations at 3, 6, 9, and 12 months were analyzed using models with treatment, study, and their interaction as factors. Changes in the plasma cortisol concentration after 3 and 12 months were analyzed using two-way analysis of variance with treatment and study number as factors. The proportions of patients with normal ACTH tests at 3 and 12 months were analyzed using models with treatment, study, and their interaction as factors. Adverse events were descriptively summarized by body system, preferred term and severity; and by body system, preferred term and relationship to study drug. Adverse events with an incidence of 3% or more in either treatment group, and glucocorticosteroid-associated adverse events were analyzed with two-way analysis of variance with treatment and study number as the factors. All statistical tests were two-sided. p-values of less than 0.05 were considered to indicate statistical significance.

Sample Size

The sample sizes in the 4 individual maintenance studies were based on the outcome of the studies in active disease. Based on a 12-month relapse rate estimate of 50% for the placebo group, this pooled analysis had an 80% probability of detecting a significant difference if the relapse rate for the budesonide 6 mg group was 34%.

RESULTS

Patient Characteristics

Eight hundred and twelve patients with active CD who were treated with budesonide, prednisolone, or placebo during four preceding induction of remission trials were screened, of whom 380 met the eligibility criteria for the subsequent four maintenance studies (CDAI 150 at the final visit). Of these 380 patients randomized to treatment, 145 received budesonide 6 mg/day, 90 received budesonide 3 mg/day, and 145 received placebo. All 380 patients were included in the intention-to-treat population. The baseline characteristics of the three groups of patients were similar (Table 2). The combined analysis trial profile is shown in Figure 1.

Figure 1.

Trial profile. A total of 84 patients in the budesonide 6 mg/day group, 58 patients in the budesonide 3 mg/day group, and 97 patients in the placebo group withdrew prior to week 52.

Full figure and legend (33K)

Table 2. - Baseline Patient Characteristics by Treatment Group.

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Clinical Effectiveness

The combined analysis of 380 patients showed that treatment with budesonide capsules 6 mg/day significantly prolonged time in remission compared with placebo. Kaplan-Meier estimates of the survival function of the time to relapse for the two treatment groups are shown in Figure 2. The median time to relapse was 268 days for patients treated with budesonide 6 mg/day, 170 days for patients treated with budesonide 3 mg/day, and 154 days for patients treated with placebo (Table 3). There was a significant overall difference among treatment groups in the distribution of the time to relapse (p= 0.0072) as shown in Figure 3 and Table 3. Pairwise comparisons demonstrated that 6 mg/day budesonide significantly prolonged the time to relapse compared with placebo (p= 0.0024), whereas the 3 mg/day budesonide dose did not (p= 0.28). There was no significant difference between the 6 mg/day budesonide and the 3 mg/day budesonide treatment groups for time to relapse (p= 0.052). Similar results were seen with the major secondary outcome variables, time to relapse or discontinuation and time in study (Table 3).

Figure 2.

Kaplan-Meier estimates for proportion of patients in the budesonide 6 mg/day, budesonide 3 mg/day, and placebo groups not relapsed over time.

Full figure and legend (20K)

Figure 3.

Median time to relapse for patients treated with budesonide 6 mg/day, budesonide 3 mg/day, or placebo.

Full figure and legend (17K)

Table 3. - Median Time to Relapse.

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Relapse rates were significantly lower for the budesonide 6 mg/day group compared with the placebo group at 3 months (p < 0.001) and at 6 months (p < 0.05) (Fig. 4). Although the relapse rates at 9 months and 1 yr were lower for the budesonide 6 mg/day group compared with the placebo group, they were no longer significantly different (Fig. 4). Relapse rates for patients treated with budesonide 3 mg/day were not significantly different from those of the placebo patients at any time point. The mean CDAI scores were significantly lower for the budesonide 6 mg/day group compared with the placebo and budesonide 3 mg/day groups at 3 months (p < 0.05), 6 months (p < 0.01), 9 months (p < 0.05), and 12 months (p < 0.05) (Fig. 5). The mean IBDQ scores were significantly higher for the budesonide 6 mg/day group compared with the placebo group at 3 months (p < 0.01), 6 months (p < 0.05), 9 months (p < 0.05), and 12 months (p < 0.05) (Fig. 6). The mean CRP values did not differ significantly among the three treatment groups at any time point.

Figure 4.

The proportion of patients in the budesonide 6 mg/day, budesonide 3 mg/day, and placebo groups that relapsed at 3, 6, 9, and 12 months. *p < 0.001, ^†p < 0.05.

Full figure and legend (17K)

Figure 5.

The mean CDAI scores in the budesonide 6 mg/day, budesonide 3 mg/day, and placebo groups at 3, 6, 9, and 12 months. *p < 0.05, ^†p < 0.01.

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Figure 6.

The mean IBDQ scores in the budesonide 6 mg/day, budesonide 3 mg/day, and placebo groups at 3, 6, 9, and 12 months. *p < 0.01, ^†p < 0.05.

Full figure and legend (22K)

Safety

Four patients out of 380 could not be assessed for the occurrence of adverse events (case report form missing for 1 placebo patient, case report form not completed for 1 budesonide 3 mg patient, and 1 placebo patient and 1 budesonide 3 mg patient lost to follow-up). The remaining 376 patients were included in the safety analysis. The budesonide 6 mg treatment group was treated on average 7 wk longer than the placebo patients; however, in the adverse events analysis, no adjustment had been made for exposure time. The percentage of patients reporting any adverse event was similar between the budesonide 6 mg and placebo groups, 81 and 78%, respectively. The corresponding percentage of patients having adverse events in the budesonide 3 mg group was somewhat lower (67%). The incidence of adverse events over time was also similar between the budesonide 6 mg group and the placebo group, 14.6 and 14.9 adverse events/1,000 treatment days, respectively, while it was slightly lower (10.8 adverse events/1,000 treatment days) in the budesonide 3 mg group.

The most commonly reported adverse events in all treatment groups were GI symptoms. The percentage of patients with GI adverse events was 41% for the budesonide 3 mg/day group, 44% for the budesonide 6 mg/day group, and 50% for the placebo group. The adverse events that occurred at a frequency 5% in at least one of the treatment groups are shown in Table 4.

Table 4. - Adverse Events and Treatment Emergent Glucocorticosteroid Side Effects by Percentage of Patients Reporting Adverse Events.

Full table

At each visit, patients were evaluated for a number of possible glucocorticosteroid side effects: bruising easily, acne, moon face, hirsutism, swollen ankles, buffalo hump, skin striae, and in 1 study, depression, mood swings, insomnia, and hair loss (Table 4). The majority of glucocorticosteroid side effects occurred at similar rates among all treatment groups; acne (p= 0.045) and moon face (p= 0.030) were significantly more common among patients treated with budesonide 6 mg/day than patients treated with placebo.

The majority of AEs were mild to moderate in intensity. The proportion of patients with serious adverse events (SAEs) was evenly distributed among the treatment groups; 11% of patients in the budesonide groups and 12% in the placebo group. The majority of the SAEs were CD symptoms requiring hospitalization. None of the SAEs were considered causally related to budesonide treatment. No deaths were reported.

DISCUSSION

There is a widely held belief that corticosteroids are not effective for maintenance of remission in patients with CD. This belief is based on controlled trials that demonstrated low doses of oral corticosteroids are not effective for maintaining either medically or surgically induced remission in patients with CD (^4,5,19,20). Nevertheless, it is recognized clinically that many patients who initially respond to corticosteroid therapy and who relapse with corticosteroids tapering can be maintained in an asymptomatic state by long-term corticosteroid therapy with prednisone 10–30 mg/day or its equivalent (^21,22). Such patients are termed "steroid-dependent." One placebo-controlled study did demonstrate efficacy for low-dose corticosteroid maintenance therapy (6-month treatment period) with 6-methylprednisolone 0.25 mg/kg/day in asymptomatic patients with elevated laboratory markers of inflammation, with the clinical benefit attributed to suppression of active subclinical inflammation rather than maintenance of remission (²³).

Oral budesonide, by virtue of its safety profile, offers the opportunity to reassess the belief that corticosteroids are not effective for maintenance therapy. The present study, a combined analysis of four similar long-term trials, demonstrates that treatment with budesonide capsules 6 mg/day is significantly more effective than placebo in prolonging time in remission for patients with CD. Taken individually, these 4 studies showed favorable trends for budesonide capsules 6 mg/day as a long-term therapy; however, significant differences compared with placebo were not consistently observed, primarily because of small sample sizes since the number of patients enrolled was determined by the percentage of patients who achieved clinical remission in the preceding induction of remission studies. Because inadequate sample size was anticipated for all four maintenance trials, a pooled analysis was intended at the outset. There was a significant overall difference among treatment groups in the distribution of relapse over time; compared with placebo, budesonide 6 mg/day significantly prolonged time to relapse. Median time to relapse was 268 days for patients treated with budesonide 6 mg daily, 170 days for patients treated with budesonide 3 mg daily, and 154 days for patients treated with placebo. Remission rates at 3 and 6 months were significantly greater in the group receiving budesonide 6 mg/day than in the placebo group. At 9 and 12 months, however, remission rates were not significantly different in the three treatment groups.

These results must be put in the context of a number of other maintenance trials with budesonide. Oral budesonide capsules 6 mg/day are more effective than placebo or mesalamine 3 g/day for maintenance of remission in patients with steroid-dependent CD (^24,25); and oral pH-modified release budesonide 6–18 mg/day is effective for the short-term maintenance of remission in patients with prednisolone-induced remission (²⁶). Maintenance therapy with a variable dose of oral budesonide capsules at a dose of 0–9 mg/day to maintain symptomatic remission results in similar control of disease activity as oral budesonide capsules at a fixed dose of 6 mg/day (²⁷) or prednisolone 0–40 mg/day adjusted to disease activity (²⁸). Maintenance therapy with oral budesonide capsules 6–9 mg/day resulted in a similar clinical remission rate at 1 yr as azathioprine 2.2 mg/kg/day, but azathioprine resulted in greater endoscopic remission (²⁹). Finally, neither oral budesonide capsules nor oral pH-modified release budesonide 3–6 mg/day were effective for postoperative maintenance of remission in patients with surgically induced remission (^30,31).

One of the major challenges in treating the patient with CD is providing symptomatic relief without detrimental side effects, such as those seen with systemic glucocorticosteroids. Administration of budesonide 6 mg daily over 52 wk was overall safe and well tolerated. The incidence of AEs with budesonide 6 mg was similar to that of placebo, both regarding glucocorticosteroid-associated side effects and the overall AE profile. The majority of AEs found in this analysis reflected symptoms of CD. No new types of AEs were reported and the majority of AEs were mild to moderate in intensity. Notably, none of the serious AEs detected in this analysis were considered causally related to budesonide treatment, and no deaths were reported. It should be noted that in another study, maintenance therapy with a variable dose of oral budesonide capsules (0–9 mg/day) to maintain symptomatic remission over 2 yr did not result in a clinically significant decrease in bone mineral density (²⁸).

To summarize, this combined analysis of 4 long-term studies demonstrates that budesonide capsules, 6 mg daily, significantly prolongs time to relapse in patients who have medically induced remission of CD. Other controlled trials have demonstrated that budesonide 6 mg/day is effective for maintaining remission in steroid-dependent patients (which includes budesonide-dependent patients), that budesonide adjusted from 0 to 9 mg/day according to disease activity can maintain symptomatic remission in a majority of patients, and that long-term treatment with budesonide 6–9 mg/day is safe and does not result in osteoporosis. Thus, long-term treatment with budesonide 6 mg/day may be a therapeutic alternative in budesonide-treated patients who experience an early relapse or who become budesonide dependent.

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Acknowledgements

William Sandborn, Robert Löfberg, Brian Feagan, and Stephen Hanauer have served as consultants for AstraZeneca. This work was supported by a research grant from AstraZeneca, Wayne, PA, United States.