ORF37-01 - Dual-dose Cosyntropin Stimulation Testing to Assess HPA-axis Safety and Identify Non-Study Corticosteroid Exposure in a Phase 3 Ulcerative Colitis Trial

Introduction: Corticosteroids are widely used in non-endocrine specialties, but baseline HPA-axis status is rarely, if ever, considered due to the acute nature of the target illness. This often leaves the endocrinologist without key information to assess the impact of steroidal treatments. Adrenal dysfunction and treatment-emergent suppression may be difficult to distinguish in clinical trials. In CESSA, a phase 3 trial of next-generation hydrocortisone acetate (ngHCA) 90 mg rectal suppositories for ulcerative colitis (UC), we implemented complementary cosyntropin stimulation protocols to distinguish baseline adrenal disease from treatment-emergent secondary suppression and enhance safety monitoring.

Methods: CESSA (NCT04469686) was a randomized, double-blind, placebo-controlled, multinational study in adults with confirmed UC of the rectum. Participants (N = 200) were randomized to ngHCA 90 mg once daily (QD), twice daily (BID), or placebo BID for 28 days, followed by a 10-day taper. Non-study corticosteroid use was prohibited. Screening used standard-dose 250 µg cosyntropin to exclude primary adrenal insufficiency. Follow-up safety visits used low-dose 1 µg cosyntropin at Day 29 (Treatment End), Day 39 (Taper End), and, if indicated, Day 53 (Safety Follow-Up) to assess secondary adrenal suppression. Pharmacokinetic (PK) sampling for plasma corticosteroid levels was performed in the morning on Days 1, 15, and 28.

Results: Twenty-five participants were referred for targeted Safety Follow-Up. Overall, 104/200 showed HPA-axis alteration during the study. Three placebo-randomized participants had persistent secondary adrenal suppression requiring endocrinology referral, indicating non-study corticosteroid exposure. All participants receiving active study drug (QD and BID), recovered HPA-axis function by the end of the targeted safety period (Day 53).

Discussion: Dual-dose cosyntropin testing provided a practical framework for HPA-axis safety assessment in a non-endocrine corticosteroid trial. Standard-dose testing excluded baseline primary adrenal insufficiency, whereas low-dose testing allowed focused evaluation of subtle secondary suppression during follow-up. Serial testing, including PK testing results (cortisol), identified unexpected adrenal suppression in placebo-treated participants, indicating non-study corticosteroid exposure that may confound both safety and efficacy assessments. Identifying HPA-axis alterations in participants randomized to active treatment was an important safety objective, and recovery of HPA-axis function in all active-treatment participants at Day 53 was reassuring. Trials using corticosteroids, or in which corticosteroid exposure may affect outcomes, including non-oral formulations and repeated or prolonged use, should incorporate strategies to monitor HPA-axis safety and data integrity.

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