Mild to Moderate Crohn's Disease: Budesonide and Mesalamine
Mild to Moderate Crohn's Disease: Budesonide and Mesalamine
Background & Aims: Comparative data on budesonide vs mesalamine for the treatment of mild-to-moderately active Crohn's disease (CD) are sparse. We assessed the efficacy and safety of each therapy in patients with mildly to moderately active CD.
Methods: We performed a randomized, double-blind, double-dummy, 8-week, multicenter study in which 309 patients with mildly to moderately active CD received pH-modified-release oral budesonide (9 mg/day once daily or 3 mg/day 3 times daily) or Eudragit-L– coated oral mesalamine (4.5 g/day).
Results: The primary efficacy variable, clinical remission (defined as Crohn's Disease Activity Index ≤150), at the final visit occurred in 69.5% (107 of 154) of patients given budesonide vs 62.1% (95 of 153) of patients given mesalamine (difference, 7.4%; 95% repeated confidence interval, –4.6% to 18.0%; P = .001 for noninferiority). Clinical remission rates did not differ significantly between the 2 budesonide groups. Treatment response, defined as Crohn's Disease Activity Index of 150 or less and/or a decrease of 70 or more (Δ70) or 100 or more (Δ100) points from baseline to final visit, did not differ significantly between patients given budesonide vs mesalamine (Δ70, P = .11; Δ100, P = .15), or between the 2 budesonide groups (Δ70, P = .38; Δ100, P = .78). No other efficacy end points differed significantly between groups. Discontinuation because of adverse events occurred in 3% and 5% of budesonide- and mesalamine-treated patients, respectively. There were no clinically relevant differences in adverse events between the 2 budesonide groups.
Conclusions: Budesonide (9 mg/day) was numerically, but not statistically, more effective than Eudragit-L–coated mesalamine (4.5 g/day) in patients with mildly to moderately active CD. Budesonide (9 mg/day), administered once daily, was as effective as the standard (3 times daily) regimen.
Uncertainty about the etiology of Crohn's disease (CD) means that treatment decisions are made empirically. Selecting the appropriate regimen for an individual patient, however, can be complex because it needs to take into account the activity, localization, and behavior of the disease; the balance between drug potency and adverse events; previous response to treatment; and the presence of extraintestinal manifestations or complications. Recently, guidelines from the European Crohn's and Colitis Organisation recommended that mildly active localized ileocecal CD should be treated with budesonide 9 mg/day based on evidence that it offers superior efficacy to placebo and mesalamine. For moderately active, localized ileocecal disease, the European Crohn's and Colitis Organisation guidelines recommend treatment with either budesonide 9 mg/day or systemic corticosteroids. Budesonide has a superior side-effect profile to conventional steroid therapy because of its relatively low bioavailability, and is better able to preserve adrenal function and bone mass. Superior tolerability might be attributed to extensive first-pass metabolism of budesonide by cytochrome P450 3A (CYP3A) enzymes and to gastrointestinal efflux mediated by P-glycoprotein, a product of the multidrug resistance 1 gene (MDR1). Mesalamine is regarded as showing only limited value in mild-to-moderately active CD on the basis of a metaanalysis of 3 studies conducted in patients with active ileal or colonic CD that concluded that ethylcellulosecoated mesalamine 4 g/day was associated with only a marginal benefit compared with placebo.
However, only a single randomized study published by Thomsen et al a decade ago has directly compared the efficacy and safety of budesonide vs mesalamine for the management of active CD. In that trial, 182 patients with active CD (Crohn's Disease Activity Index [CDAI], 200–400) received either a controlled ileal-release budesonide formulation 9 mg once daily (OD) or 2 g ethylcellulosecoated mesalamine twice daily. After 8 weeks of treatment, clinical remission was observed significantly more frequently with budesonide than mesalamine (69% vs 45%; P = .001), a difference that was sustained at week 16 (62% vs 36%; P < .001). Since then, no comparative studies of budesonide vs mesalamine have explored the use of alternative formulations to those used in the Thomsen et al study or examined different budesonide dosing regimens.
We report here the findings of a double-blind, doubledummy study in which patients with mildly to moderately active CD were randomized to pH-modified-release budesonide (9 mg/day, given in a single dose or 3 times daily) or Eudragit-L–coated (Evonik, Essen, Germany) oral mesalamine tablets at a dose of 4.5 g/day. The primary objective was to assess the efficacy and safety of each regimen during an 8-week treatment period.
Abstract and Introduction
Abstract
Background & Aims: Comparative data on budesonide vs mesalamine for the treatment of mild-to-moderately active Crohn's disease (CD) are sparse. We assessed the efficacy and safety of each therapy in patients with mildly to moderately active CD.
Methods: We performed a randomized, double-blind, double-dummy, 8-week, multicenter study in which 309 patients with mildly to moderately active CD received pH-modified-release oral budesonide (9 mg/day once daily or 3 mg/day 3 times daily) or Eudragit-L– coated oral mesalamine (4.5 g/day).
Results: The primary efficacy variable, clinical remission (defined as Crohn's Disease Activity Index ≤150), at the final visit occurred in 69.5% (107 of 154) of patients given budesonide vs 62.1% (95 of 153) of patients given mesalamine (difference, 7.4%; 95% repeated confidence interval, –4.6% to 18.0%; P = .001 for noninferiority). Clinical remission rates did not differ significantly between the 2 budesonide groups. Treatment response, defined as Crohn's Disease Activity Index of 150 or less and/or a decrease of 70 or more (Δ70) or 100 or more (Δ100) points from baseline to final visit, did not differ significantly between patients given budesonide vs mesalamine (Δ70, P = .11; Δ100, P = .15), or between the 2 budesonide groups (Δ70, P = .38; Δ100, P = .78). No other efficacy end points differed significantly between groups. Discontinuation because of adverse events occurred in 3% and 5% of budesonide- and mesalamine-treated patients, respectively. There were no clinically relevant differences in adverse events between the 2 budesonide groups.
Conclusions: Budesonide (9 mg/day) was numerically, but not statistically, more effective than Eudragit-L–coated mesalamine (4.5 g/day) in patients with mildly to moderately active CD. Budesonide (9 mg/day), administered once daily, was as effective as the standard (3 times daily) regimen.
Introduction
Uncertainty about the etiology of Crohn's disease (CD) means that treatment decisions are made empirically. Selecting the appropriate regimen for an individual patient, however, can be complex because it needs to take into account the activity, localization, and behavior of the disease; the balance between drug potency and adverse events; previous response to treatment; and the presence of extraintestinal manifestations or complications. Recently, guidelines from the European Crohn's and Colitis Organisation recommended that mildly active localized ileocecal CD should be treated with budesonide 9 mg/day based on evidence that it offers superior efficacy to placebo and mesalamine. For moderately active, localized ileocecal disease, the European Crohn's and Colitis Organisation guidelines recommend treatment with either budesonide 9 mg/day or systemic corticosteroids. Budesonide has a superior side-effect profile to conventional steroid therapy because of its relatively low bioavailability, and is better able to preserve adrenal function and bone mass. Superior tolerability might be attributed to extensive first-pass metabolism of budesonide by cytochrome P450 3A (CYP3A) enzymes and to gastrointestinal efflux mediated by P-glycoprotein, a product of the multidrug resistance 1 gene (MDR1). Mesalamine is regarded as showing only limited value in mild-to-moderately active CD on the basis of a metaanalysis of 3 studies conducted in patients with active ileal or colonic CD that concluded that ethylcellulosecoated mesalamine 4 g/day was associated with only a marginal benefit compared with placebo.
However, only a single randomized study published by Thomsen et al a decade ago has directly compared the efficacy and safety of budesonide vs mesalamine for the management of active CD. In that trial, 182 patients with active CD (Crohn's Disease Activity Index [CDAI], 200–400) received either a controlled ileal-release budesonide formulation 9 mg once daily (OD) or 2 g ethylcellulosecoated mesalamine twice daily. After 8 weeks of treatment, clinical remission was observed significantly more frequently with budesonide than mesalamine (69% vs 45%; P = .001), a difference that was sustained at week 16 (62% vs 36%; P < .001). Since then, no comparative studies of budesonide vs mesalamine have explored the use of alternative formulations to those used in the Thomsen et al study or examined different budesonide dosing regimens.
We report here the findings of a double-blind, doubledummy study in which patients with mildly to moderately active CD were randomized to pH-modified-release budesonide (9 mg/day, given in a single dose or 3 times daily) or Eudragit-L–coated (Evonik, Essen, Germany) oral mesalamine tablets at a dose of 4.5 g/day. The primary objective was to assess the efficacy and safety of each regimen during an 8-week treatment period.
