Regulatory Decision Summary for CORTIMENT

Health Canada considers that the benefit-harm-uncertainty profile of Cortiment is favorable for the induction of remission in patients with active, mild to moderate ulcerative colitis (UC).

The data supporting the clinical safety and efficacy of Cortiment relied primarily on two randomized, double-blind, pivotal Phase III placebo-controlled clinical trials carried out in patients with active, mild to moderate UC. A total of 970 adult patients were enrolled in the two studies combined, with an Ulcerative Colitis Disease Activity Index (UCDAI) of ≥ 4 and ≤ 10. A total of 899 of these patients had histology consistent with active UC.

Both studies compared Cortiment 9 milligram (mg) and 6 mg with placebo and included an active control arm (mesalamine 2.4 grams [g] daily in Study 1, and another budesonide formulation [9 mg daily] in Study 2). Overall, 232 patients were treated with Cortiment 9 mg, 230 patients with Cortiment 6 mg, and 210 patients with placebo. The additional active control arms were of lesser interest since they were not accounted for in the calculation of statistical power. The primary efficacy endpoint was induction of remission after 8 weeks of treatment. Remission was defined as an UCDAI ≤ 1, with sub-scores of 0 for rectal bleeding, stool frequency, and mucosal appearance, and with a ≥ 1 point reduction in an endoscopy-only score. In each of the two studies, after 8 weeks of treatment, the proportion of patients treated with Cortiment 9 mg achieving clinical remission was statistically significantly higher (17.9% on Study 1, and 17.4% in Study 2) as compared to patients treated with placebo (7.4% on Study 1, and 4.5% in Study 2), for a statistically significant (p≤ 0.014) difference of 10.4% in Study 1, and 12.9% in Study 2. Though the magnitude of the difference was moderate, it is considered to be clinically significant, given the stringency of the primary endpoint, the seriousness of the condition, and the limitations of treatment alternatives.

The clinical safety data, mainly derived from these two clinical trials, indicate that most adverse events (AEs) were mild to moderate in severity with 7% of patients reporting severe AEs. The rates of AEs were not significantly higher with Cortiment (56.5%) as compared to placebo (53.5%). The most frequently reported AEs were in the gastrointestinal category (32% of patients), with worsening of UC as the most frequent (13% with Cortiment 9 mg, 14% with placebo), followed by nausea. Headache was reported a similar rates (11%) between Cortiment 9mg and placebo, whereas decreased blood cortisol was reported in 4.3% of patients treated with Cortiment 9mg compared to 0.4% of patients treated with placebo. Serious AEs were reported at similar rates in patients treated with Cortiment 9 mg (2.7%) as compared to placebo (3.1%). AEs leading to discontinuation were also reported at similar rates with Cortiment 9 mg (15.3%) and placebo (16.7%), with the most frequent being "Ulcerative colitis" which was reported in 11% to 12% of patients in both the Cortiment 9 mg and placebo groups.

Laboratory tests (low morning cortisol levels, and impaired adrenal response) indicated that some degree of adrenal insufficiency may have occurred in some patients, however, these laboratory tests did not clearly translate into actual clinical effects, since potential corticosteroid signs or symptoms were not reported significantly more frequently with Cortiment 9 mg (10.2%) as compared to placebo (10.5%). In addition, these effects are not unexpected for corticosteroids. This suggests that Cortiment may act partially locally, with some systemic effects.

Based on the evidence provided, the anticipated benefits of Cortiment are considered to outweigh its potential harms and uncertainties in patients with active, mild to moderate UC under the conditions of use recommended in the Product Monograph at this time.