Study protocol for a prospective, multicentre study of hypercortisolism in patients with difficult-to-control type 2 diabetes (CATALYST): prevalence and treatment with mifepristone

• Published in: BMJ open Vol. 14; no. 7; p. e081121
• Main Authors: DeFronzo, Ralph A, Auchus, Richard J, Bancos, Irina, Blonde, Lawrence, Busch, Robert S, Buse, John B, Findling, James W, Fonseca, Vivian A, Frias, Juan P, Hamidi, Oksana, Handelsman, Yehuda, Pratley, Richard E, Rosenstock, Julio, Tudor, Iulia Cristina, Moraitis, Andreas G, Einhorn, Daniel
• Format: Journal Article
• Language: English
• Published: England British Medical Journal Publishing Group 16.07.2024; BMJ Publishing Group LTD; BMJ Publishing Group
• Subjects: Adrenal disorders; Adult; Clinical Trial; Cushing syndrome; Cushing Syndrome - drug therapy; Diabetes; DIABETES & ENDOCRINOLOGY; Diabetes and Endocrinology; Diabetes Mellitus, Type 2 - drug therapy; Double-Blind Method; Endocrine tumours; Female; General diabetes; General endocrinology; Glycated Hemoglobin - analysis; Glycated Hemoglobin - metabolism; Hormone Antagonists - therapeutic use; Hormones; Humans; Hydrocortisone - blood; Hypertension; Insulin resistance; Male; Medical imaging; Metabolism; Middle Aged; Mifepristone - therapeutic use; Mortality; Multicenter Studies as Topic; Neuroendocrine tumors; Patients; Plasma; Prevalence; Prospective Studies; Protocol; Tumors; DIABETES & ENDOCRINOLOGY; Clinical Trial; General diabetes; Adrenal disorders; Endocrine tumours; General endocrinology
• ISSN: 2044-6055; 2044-6055
• DOI: 10.1136/bmjopen-2023-081121

IntroductionEven with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies indicate that in >10% of individuals with difficult-to-control T2D, hypercortisolism may be an underlying contributing cause. To better understand the prevalence of hypercortisolism and the impact of its treatment on T2D and associated comorbidities, we describe the two-part Hyper c ortisolism in P at ients with Difficult to Control Type 2 Di a betes Despite Receiving Standard-of-Care Therapies: Preva l ence and Treatment with Korl y m® (Mifepri st one) (CATALYST) trial.Methods and analysisIn part 1, approximately 1000 participants with difficult-to-control T2D (haemoglobin A1c (HbA1c) 7.5%–11.5% despite multiple therapies) are screened with a 1 mg dexamethasone suppression test (DST). Those with post-DST cortisol >1.8 µg/dL and dexamethasone level ≥140 ng/dL are identified to have hypercortisolism (part 1 primary endpoint), have morning adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) measured and undergo a non-contrast adrenal CT scan. Those requiring evaluation for elevated ACTH are referred for care outside the study; those with ACTH and DHEAS in the range may advance to part 2, a randomised, double-blind, placebo-controlled trial to evaluate the impact of treating hypercortisolism with the competitive glucocorticoid receptor antagonist mifepristone (Korlym®). Participants are randomised 2:1 to mifepristone or placebo for 24 weeks, stratified by the presence/absence of an abnormal adrenal CT scan. Mifepristone is dosed at 300 mg once daily for 4 weeks, then 600 mg daily based on tolerability and clinical improvement, with an option to increase to 900 mg. The primary endpoint of part 2 assesses changes in HbA1c in participants with hypercortisolism with or without abnormal adrenal CT scan. Secondary endpoints include changes in antidiabetes medications, cortisol-related comorbidities and quality of life.Ethics and disseminationThe study has been approved by Cleveland Clinic IRB (Cleveland, Ohio, USA) and Advarra IRB (Columbia, Maryland, USA). Findings will be presented at scientific meetings and published in peer-reviewed journals.Trial registration number NCT05772169.