Study design of a phase 3, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of osilodrostat in patients with cushing's disease

Osilodrostat is an oral inhibitor of 11|3‐hydroxylase (CYP11B1), the enzyme that catalyzes the last step in cortisol biosynthesis. It also inhibits aldosterone synthase (CYP11B2) and thus inhibits both cortisol and aldosterone synthesis. In a phase 2 study in patients with Cushing's disease, osilodrostat treatment resulted in normalization of mean urinary free cortisol (mUFC) in 78.9% (15/19) of patients at week 22. Mean UFC normalization was maintained up to month 19 in most of the patients who entered the extension phase of this study; overall response at month 19 was 75% (12/16); however, it was 93.8% (15/16) when the last observations were carried forward (LOCF). Osilodrostat was well tolerated in this study. The present phase 3 study aims to confirm the efficacy and safety of osilodrostat in patients with uncontrolled Cushing's disease. Adult patients with confirmed diagnosis of Cushing's disease (persistent or recurrent hypercortisolism) or de novo Cushing's disease if not surgical candidates, with mUFC > 1.3 times ULN (upper limit of normal) and ACTH > LLN (lower limit of normal) will be included. Planned enrollment is 69 patients. This international, phase 3, multicenter, 48‐week study has an initial 12‐week randomized, double‐blind, placebo‐controlled period (period 1) followed by a single‐arm, open‐label treatment period (period 2). In period 1 (week 1���12), patients will be randomized in 2:1 ratio to osilodrostat or placebo starting with 2 mg bid. Dose adjustments, ranging between 1 mg qod and 20 mg bid, can be made to normalize mUFC levels or to address safety issues. In period 2 (week 13‐48), with a single‐arm, open‐label design, all patients will start on osilodrostat 2 mg bid, except patients on osilodrostat or matching placebo < 2 mg bid at the end of period 1, who will continue with their most recent dose. Dose escalation is permitted up to 30 mg bid. At week 48, patients have the option to enter an open‐label extension phase that continues up to week 96. The primary endpoint is the proportion of randomized patients with a complete response (mUFC < ULN) at week 12. Key secondary endpoint is the proportion of enrolled patients with mUFC < ULN at week 36 in all patients treated with osilodrostat. Other secondary endpoints include changes in cardiovascular and metabolic parameters, physical features, bone mineral density (BMD), health related quality of life (HRQoL), safety and tolerability of osilodrostat, and pharmacokinetic exposure to osilodrostat. This is the first phase 3 study in patients with Cushing's disease, with an upfront blinded, placebo‐controlled period. The open label period in this study will enable long‐term evaluation of the efficacy and safety of osilodrostat..