Budesonide MMX for the Induction of Remission of Mild to Moderate Ulcerative Colitis: A Pooled Safety Analysis

Background and aims: Cumulative safety and tolerability of budesonide MMX, a once-daily oral corticosteroid for inducing mild to moderate ulcerative colitis remission, was examined. Methods: Data from three randomized, double-blind, placebo-controlled, phase II or III studies [budesonide MMX 9mg, 6mg, or 3mg for 8 weeks]; one phase II study [randomisation to budesonide MMX 9mg or placebo for 4 weeks, then open-label budesonide MMX 9mg for 4 weeks]; and one open-label study [budesonide MMX 9mg for 8 weeks] were pooled. Results: Patients randomised to budesonide MMX 9mg [n = 288], 6mg [n = 254], or placebo [n = 293] had similar rates of adverse events [AEs] [27.1%, 24.8%, and 23.9%, respectively] and serious AEs [2.4%, 2.0%, and 2.7%, respectively]; treatment-related AEs and serious AEs were reported by 11.8% and 13.5%, and 5.9% and 2.2%, respectively, of patients receiving budesonide MMX 3mg [n = 17] or open-label budesonide MMX 9mg [n = 89]. Mean morning plasma cortisol concentrations were normal from baseline to final visit across randomised groups; in patients receiving open-label budesonide, mean cortisol concentration was 129.9 nmol/l after 4 weeks, returning to normal concentrations at final visit. Budesonide MMX was not associated with an overall increased risk for glucocorticoid-related adverse effects. Conclusions: Budesonide MMX 9mg was associated with normal mean cortisol concentrations at final visit and an AE incidence comparable to placebo. Overall, budesonide MMX was safe and well tolerated for inducing remission of patients with mild to moderate ulcerative colitis.

rates for UC, 2 and direct medical costs were estimated to be > US $2 billion in 2004. 3 Current treatment guidelines, edited by the professional bodies or associations up to 2012, recommend 5-aminosalicylic acid  as first-line therapy for the induction of remission in patients with mild to moderate UC. 4,5 Systemic corticosteroids are usually required as the disease progresses, but are associated with safety concerns, including adrenal suppression, infections, ophthalmic effects [eg cataracts, glaucoma], and mood changes. 4,6 The potent, second-generation corticosteroid budesonide may have an improved safety profile over conventional corticosteroids because of its low [10-15%] systemic bioavailability, attributable to its extensive presystemic elimination in the gastrointestinal tract and liver. 7 The affinity of budesonide for the glucocorticoid receptor is approximately 8.5 times higher than that of dexamethasone 8 and 15 times higher than that of prednisolone. 9 Because of its rapid elimination, a form of extended-release budesonide with delayed elimination was developed that uses multi-matrix [MMX ® ] technology [budesonide MMX]. 10,11 In this formulation, the active drug is embedded in an inner lipophilic [stearic acid] matrix with an overlying amphiphilic [lecithin] matrix and surrounded by a hydrophilic [hydroxypropylcellulose] matrix-forming polymer. The entire tablet is coated with gastro-resistant methacrylic acid copolymers that dissolve at a pH ≥ 7, 7,11 thus targeting release of > 95% of active budesonide throughout the entire colon. 7 The efficacy and safety of budesonide MMX has been reported in two phase III, randomised, placebo-controlled studies. In the CORE I 12 and CORE II 13 studies, budesonide MMX 9 mg was significantly more efficacious than placebo for the induction of clinical and endoscopic remission and symptom resolution [ie achievement of Ulcerative Colitis Disease Activity Index [UCDAI] rectal bleeding and stool frequency subscale scores of 0] in patients with mild to moderate UC. Given the potential safety concerns associated with the use of corticosteroids, the objective of the current analysis was to conduct a safety and tolerability assessment of budesonide MMX for the induction of remission in patients with mild to moderate UC, by pooling data from five clinical studies.

Patients and study design
The safety data from five clinical trials were pooled for analysis: two phase III, randomised, double-blind, placebo-controlled studies (CORE I [NCT00679432] and CORE II [NCT00679380]), 12 12,13 Briefly, patients with a UCDAI score of ≥ 4 and ≤ 10 and histological evidence of active UC received budesonide MMX 9 mg, budesonide MMX 6 mg, placebo, or reference medication once daily for 8 weeks. 12,13 Remission, the primary endpoint, was strictly defined as a total UCDAI score ≤ 1, with a rectal bleeding score of 0, stool frequency score of 0, mucosal appearance score of 0 on full colonoscopy

Statistical analyses
The safety population included all patients who received ≥ 1 dose of study drug. Descriptive statistics were used to summarise demographic and baseline disease characteristics of the safety population and safety variables. Qualitative variables were presented as category counts and percentages. Statistical comparisons of safety endpoints were performed using a Fisher's exact test, and comparisons of mean morning cortisol concentrations were performed using a t-test. Compliance was evaluated by tablet counts and calculated using the following formula: Patients were considered compliant if they took > 80% of study drug. To maintain consistency with data analysis, data collected during the last visit for patients who discontinued the study early were mapped to the final visit time point.

Patients
Overall, 648 patients received budesonide MMX 9 mg, budesonide MMX 6 mg, or budesonide MMX 3 mg, with 58.2% receiving budesonide MMX 9 mg [ Table 1]; 293 patients received placebo. Demographic and baseline disease characteristics were generally comparable across treatment groups for the randomised, controlled trials [ Table 2]. The percentage of patients with proctosigmoiditis, left-sided colitis, and extensive UC were comparable within each group and among groups, except for patients in the budesonide MMX 3 mg group, for whom these data were not collected. The majority of patients had moderate disease [UCDAI score 6-10] at baseline.
Overall exposure to the study drug was similar among treatment groups in the randomised, double-blind studies [ Table 3]. The median duration of study drug exposure for patients receiving budesonide MMX 9 mg, 6 mg, 3  The most common reason for study discontinuation in the randomised, controlled studies was treatment failure. Study discontinuation due to AEs occurred in 3.1%, 3.1%, 0%, and 3.8% of patients receiving budesonide MMX 9 mg, 6 mg, 3 mg, and placebo, respectively, in the, double-blind studies; 2.2% of patients receiving budesonide MMX 9 mg in the open-label studies discontinued on account of AEs.

Adverse events
The percentage of patients with any AE was generally similar among the budesonide MMX 9 mg and 6 mg groups [54.5% vs 60.6%, respectively] and placebo [50.5%] in the randomised, double-blind studies, and in the budesonide MMX 9 mg group of the open-label studies [50.6%; Table 4]. Patients receiving budesonide MMX 3 mg reported the fewest AEs [35.3%]. The frequency of drug-related AEs was similar among the budesonide MMX 9 mg, 6 mg, and placebo groups in the randomised, double-blind studies; patients receiving budesonide MMX 3 mg or budesonide MMX 9 mg in the openlabel studies had the fewest drug-related AEs. The most frequently reported AEs were UC, headache, and nausea in patients receiving budesonide MMX 9 mg, 6 mg, or placebo in the randomised, double-blind studies, whereas decreased blood cortisol concentrations and urinary tract infection were the most commonly reported AEs in the open-label studies of budesonide MMX 9 mg. The percentage of patients with infections was generally similar among the budesonide MMX 9 mg, 6 mg, and placebo groups [ Overall, SAEs were reported by 2.4% of patients across all treatment groups; the percentage of patients with SAEs was similar across groups [ Table 4]. Serious AEs led to study discontinuation in 1.9%, 1.6%, and 1.4% of patients receiving budesonide MMX 9 mg, 6 mg, or placebo, respectively, across randomised and open-label studies. No patient receiving budesonide MMX 3 mg experienced an SAE leading to study discontinuation. UC-related events [eg worsening of UC] were the most common SAE leading to withdrawal in patients receiving budesonide MMX 9 mg, 6 mg, or placebo. No deaths were reported.

Plasma cortisol concentrations
In the randomised, double-blind studies, mean morning plasma cortisol concentrations decreased in a dose-dependent manner from

Potential glucocorticoid-related adverse effects
The incidence of potential glucocorticoid-related adverse effects was < 10% across all treatment groups [ Table 5]. There was no apparent dose-related increase in potential glucocorticoid-related adverse effects following treatment with budesonide MMX. Further, the incidence of potential glucocorticoid-related adverse effects was similar when mean morning cortisol concentrations at final visit were distributed across quartiles. When patients with low morning plasma cortisol concentrations [< 138 nmol/l] at the final visit were selectively examined, mood and sleep changes were the most frequently reported potential glucocorticoid-related adverse effects among patients who received budesonide MMX 9 mg, 6 mg, or placebo [ Table 6]. In the budesonide MMX 3 mg group, one patient reported fluid retention.

Discussion
Budesonide MMX is a second-generation oral corticosteroid indicated for the induction of remission in patients with active, mild to moderate UC. 10 In a pooled safety analysis of five clinical studies, budesonide MMX administered for up to 8 weeks demonstrated a favourable safety and tolerability profile for the induction of remission in patients with active, mild to moderate UC. The overall AE profile in patients taking budesonide MMX was comparable to that of those taking placebo. Pooling of safety data for 648 patients receiving budesonide MMX 9 mg, 6 mg, or 3 mg provided a more robust evaluation of the safety of budesonide MMX and allowed for greater accuracy in estimating the incidence of drug-related AEs,  especially when compared with assessments of the studies individually. The findings of this pooled analysis support the short-term safety and tolerability of budesonide MMX for the induction of remission in patients with mild to moderate UC.
The frequency and intensity of AEs were generally comparable across treatment groups, with the fewest AEs reported in the budesonide MMX 3 mg group; however, this treatment group also included the fewest patients [n = 17]. Suppression of the immune system may occur during treatment with systemic corticosteroids, 6 thus increasing the risk of infection in patients. However, this analysis suggested no apparent dose-related increase in the incidence of infections. Further, patients receiving budesonide MMX 9 mg or 6 mg had a rate of infection similar to that of patients receiving placebo, and patients receiving budesonide MMX 3 mg had the lowest incidence of infection. The occurrence of SAEs during treatment with budesonide MMX was infrequent, with patients in randomised, double-blind studies in the budesonide MMX 9 mg group reporting the greatest frequency of SAEs [2.4%]. The AE profile of patients in this pooled safety analysis is comparable to previous reports of patients with left-sided UC or Crohn's disease who received once-daily oral budesonide 9 mg for 8 to 16 weeks. [14][15][16] Decreased plasma cortisol concentrations and glucocorticoid-related adverse effects [e.g. moon face, striae rubrae, mood changes, sleep changes] are associated with treatment with systemic   20 which showed that patients receiving oral budesonide 9 mg had a decrease in median morning cortisol concentrations to 135.2 nmol/l after 4 weeks, that returned to normal after 8 weeks. Mean cortisol concentrations after 4 weeks following treatment with budesonide MMX 9 mg in the open-label studies were decreased compared with those for patients who received budesonide MMX 9 mg in the randomised, controlled studies; this finding may be due to the number of patients who had previously completed 8 weeks of treatment with budesonide MMX 9 mg or 6 mg in the CORE I study. Results of this analysis suggest that short-term [up to 8 weeks] treatment with budesonide MMX had a minimal effect on the hypothalamic-pituitary-adrenal axis, a finding that is consistent with the pharmacodynamic activity of budesonide. The minimal systemic exposure of budesonide is due to its > 90% first-pass hepatic metabolism. 21 Glucocorticoid-related adverse effects occurred in < 10% of patients in each treatment group. Patients with low [< 138 nmol/l] plasma cortisol concentrations at final visit did not appear to be at increased risk for potential glucocorticoid-related adverse effects compared with placebo. However, it is difficult to draw firm conclusions given the small number of patients in the budesonide MMX 3 mg and placebo groups.
Several limitations of this analysis should be noted, including differences in study design among the clinical trials analysed [eg randomised, controlled studies; open-label studies] and the wide variation in the number of patients across budesonide MMX treatment groups [eg budesonide MMX 3 mg, n = 17; budesonide MMX 6 mg, n = 254; vs budesonide MMX 9 mg, n = 377]. Further, the studies were not designed, and thus not sufficiently powered, to specifically evaluate safety outcomes. Although the studies included did not contribute equally to the analysis, it is reassuring that a low incidence of AEs were reported in the two large, randomised, controlled trials.
In conclusion, the findings of this pooled safety analysis demonstrate that short-term treatment with budesonide MMX for the induction of remission in patients with mild to moderate UC was well tolerated, with an AE profile comparable to placebo. Although 5-ASAs are currently the most frequently prescribed treatment for the induction of remission of mild to moderate UC, 4,5 budesonide MMX is a second-generation glucocorticosteroid indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis and may be an alternative to conventional corticosteroid in such patients.