Evaluation of Evidence of Adrenal Insufficiency in Trials of Normocortisolemic Patients Treated With Mifepristone

CONTEXT: Adrenal insufficiency (AI) is an important medical concern for clinicians when normocortisolemia is achieved during treatment of endogenous Cushing syndrome (CS). OBJECTIVE: To examine symptoms of potential AI in a large population of normocortisolemic patients without CS treated with mifepristone, a glucocorticoid receptor antagonist indicated for the treatment of patients with CS. METHODS: We conducted a pooled safety analysis of five phase 3, placebo-controlled clinical trials of normocortisolemic adults without CS but diagnosed with psychotic depression (n = 1460). Patients were treated with once-daily mifepristone 300 mg (n = 110), 600 mg (n = 471), or 1200 mg (n = 252), or placebo (n = 627) administered for 7 consecutive days. All study investigators were trained and instructed to assess for the development of AI and to report all adverse events (AEs) at each clinic visit. The incidence of (1) AI or similar terminologies and that of (2) ≥3 concurrent symptoms that could be associated with AI was evaluated. RESULTS: Mean serum cortisol and adrenocorticotropic hormone levels increased dose dependently with mifepristone treatment. There were no reports of AI and no significant differences between the mifepristone-treated and placebo groups in the incidence of patients having ≥3 AEs that could be associated with AI. CONCLUSIONS: This large pooled analysis of normocortisolemic patients without CS found no cases of AI and no differences between mifepristone therapy and placebo in the incidence of symptom combinations mimicking AI, even at the highest (1200 mg) dose. These findings further add clinically important insights to the safety and tolerability profile of mifepristone therapy.