Endocrine Abstracts

Relacorilant is a highly selective glucocorticoid receptor modulator that antagonizes the effects of excess cortisol while showing no significant affinity for the mineralocorticoid and progesterone receptors. In a Phase 2 study in patients with endogenous hypercortisolism, relacorilant demonstrated improvements in glycemic and hypertension control with no treatment-related hypokalemia or antiprogesterone effects. An international, multicenter, Phase 3 clinical trial, using randomized withdrawal after 22 weeks (22 wk) of open-label treatment, is currently underway to evaluate the efficacy and safety of relacorilant in hypercortisolism of various etiologies (GRACE Study: NCT03697109). In this study, evidence of hypercortisolism must be documented through 2 independent biochemical tests and at least 2 clinical signs and symptoms. Here, we introduce GRADIENT, a double-blind, randomized, placebo-controlled Phase 3 study in approximately 130 patients with less-severe hypercortisolism secondary to adrenal adenoma(s) or hyperplasia. Clinical entry criteria for patients 18–80 years old include a radiologically confirmed adrenal lesion, a biochemical diagnosis of autonomous cortisol secretion, and either impaired glucose tolerance/diabetes mellitus (IGT/DM) and/or hypertension. Participants will receive relacorilant (100 mg/day, titrated to 400 mg/day, as tolerated) or placebo over 22 wk. Biochemical criteria for entry into the study include serum cortisol >1.8 µg/dl after dexamethasone suppression testing and low (<15 pg/dl) or suppressed morning ACTH levels. Patients must be stable on their antidiabetic and/or antihypertensive agents for at least 4 weeks prior to the first dose of relacorilant. The primary efficacy endpoints are the mean change in AUC_glucose from baseline to 22 wk for the IGT/DM group and mean change in systolic blood pressure (based on ambulatory blood pressure monitoring) for the hypertension group. Secondary endpoints include changes in weight, waist circumference, quality of life, trabecular bone score, and coagulation markers. The safety analysis will be performed for all patients who received at least one dose of study drug. GRADIENT will be the first double-blind, randomized, placebo-controlled study to test if patients with less severe hypercortisolism secondary to cortisol-secreting adrenal adenoma(s) or hyperplasia benefit from medical treatment.