Abstract and Introduction
Background & Aims: Budesonide is a high-potency, second-generation corticosteroid designed to minimize systemic adverse consequences of conventional corticosteroids. We performed 2 randomized, phase 3 trials to evaluate the ability of budesonide rectal foam, formulated to optimize retention and provide uniform delivery of budesonide to the rectum and distal colon, to induce remission in patients with ulcerative proctitis or ulcerative proctosigmoiditis.
Methods: Two identically designed, randomized, double-blind, placebo-controlled trials evaluated the efficacy of budesonide foam for induction of remission in 546 patients with mild to moderate ulcerative proctitis or ulcerative proctosigmoiditis who received budesonide foam 2 mg/25 mL twice daily for 2 weeks, then once daily for 4 weeks, or placebo.
Results: Remission at week 6 occurred significantly more frequently among patients receiving budesonide foam than placebo (Study 1: 38.3% vs 25.8%; P = .0324; Study 2: 44.0% vs 22.4%; P < .0001). A significantly greater percentage of patients receiving budesonide foam vs placebo achieved rectal bleeding resolution (Study 1: 46.6% vs 28.0%; P = .0022; Study 2: 50.0% vs 28.6%; P = .0002) and endoscopic improvement (Study 1: 55.6% vs 43.2%; P = .0486; Study 2: 56.0% vs 36.7%; P = .0013) at week 6. Most adverse events occurred at similar frequencies between groups, although events related to changes in cortisol values were reported more frequently with budesonide foam. There were no cases of clinically symptomatic adrenal insufficiency.
Conclusions: Budesonide rectal foam was well tolerated and more efficacious than placebo in inducing remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis. ClinicalTrials.gov ID: NCT01008410 and NCT01008423.
Ulcerative proctitis (UP) and ulcerative proctosigmoiditis (UPS) are part of the spectrum of ulcerative colitis (UC), an idiopathic chronic inflammatory disease of the colon that is believed to be immune-mediated. Approximately 46% of patients with UC are diagnosed with UP or UPS.[2,3] Clinical UC symptoms include rectal bleeding, diarrhea, urgency, tenesmus, and abdominal pain. Oral or rectal mesalamine is often administered as first-line therapy.[4,5] Suppositories and liquid enemas are recommended for the induction of remission in patients with mild to moderate UP, and they can be administered alone or in combination with oral mesalamine when mild to moderate disease extends beyond the rectum.[1,6,7] However, these rectal therapies have several limitations, including difficulty of administration, retention, and limited proximal spread. For example, suppositories disperse no further than the rectum, and while liquid enemas can spread to the splenic flexure, they are difficult for patients to retain and require patients to remain recumbent for a specified period of time after administration.[1,8,9]
Although active UP and UPS can be treated effectively with systemic corticosteroids,[6,10–12] their use can result in adverse effects, including mood and sleep changes, Cushingoid appearance, weight gain, fluid retention, acne, and hirsutism; longer-term use of systemic steroids can lead to more serious adverse effects, such as increased risk of infections, decreased bone density, ocular complications (eg, glaucoma, cataracts), and adrenal insufficiency.[6,13] There remains an unmet need for therapies that can target the area of active inflammation and yet have fewer systemic effects than conventional steroids.
High-potency, second-generation corticosteroids, including budesonide and beclomethasone, can be administered either rectally or orally to produce a topical anti-inflammatory effect. Budesonide has nearly 90% first-pass hepatic metabolism, thus reducing the potential for corticosteroid-related adverse events (AEs).[13–15] A randomized, double-blind, dose-ranging study of patients with active UP or distal UC receiving budesonide enema demonstrated efficacy (ie, increased rate of remission vs placebo, improved endoscopic inflammation and histology scores relative to baseline) for up to 6 weeks. In an active comparator study of patients with active UP, UPS, or left-sided UC, budesonide enema had a safety profile similar to that of mesalamine enema, although mesalamine enema induced remission in a significantly greater percentage of patients compared with budesonide enema (77.2% vs 63.5%, respectively; P < .05). Beclomethasone foam and enema were shown to have efficacy and safety profiles similar to those observed for mesalamine foam and enema in patients with mild to moderate UP or UPS after 8 weeks.
Budesonide foam is a new rectal formulation of budesonide that optimizes drug retention and provides uniform drug delivery to the rectum and distal colon, with a maximal spread of up to 40 cm (mean, 25.4 cm). Budesonide foam had an efficacy profile comparable with that of hydrocortisone foam for treatment of UP and UPS, with no significant impact on cortisol concentrations or increased occurrence of corticosteroid-related AEs when administered for up to 8 weeks. A majority of patients with active UP or UPS preferred a steroid foam formulation to a steroid enema formulation. To evaluate the efficacy and safety of budesonide foam relative to placebo in patients with active, mild to moderate UP and UPS, we conducted 2 identically designed, 6-week, double-blind induction trials.
Gastroenterology. 2015;148(4):740-750. © 2015 AGA Institute