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

Abstract

Introduction: Even 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 analysis: In 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 dissemination: The 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.

Keywords: Adrenal disorders; Clinical Trial; DIABETES & ENDOCRINOLOGY; Endocrine tumours; General diabetes; General endocrinology.

Figure 1. Cardiovascular events and survival in a study of patients with adrenal incidentalomas. Kaplan-Meier curves showing (A) global cardiovascular events (non-fatal acute myocardial infarction, percutaneous transluminal coronary angioplasty and surgical bypass for ischaemic heart disease or ischaemic stroke) and (B) logarithmic cumulative cardiovascular survival in patients with NFA, MSH or SSH during 15 years of follow-up. Figure previously published in and reproduced with permission. MSH, pharmacological treatment for subclinical hypercortisolism; NFA, non-functional adrenal adenoma; RR, risk ratio; SSH, surgical treatment for subclinical hypercortisolism.

Figure 2. Study schema and patient flow for CATALYST. ACTH, adrenocorticotropic hormone; APRI, aspartate aminotransferase-to-platelet-ratio index; CATALYST, Hypercortisolism in Patients with Difficult to Control Type 2 Diabetes Despite Receiving Standard-of-Care Therapies: Prevalence and Treatment with Korlym^® (Mifepristone); DHEAS, dehydroepiandrosterone sulfate; DST, dexamethasone suppression test; FIB-4, fibrosis-4; HbA1c, haemoglobin A1c; T2D, type 2 diabetes.

Figure 3. Dexamethasone suppression test (DST) procedure. ^aReflex measurement. ACTH, adrenocorticotropic hormone; DHEAS, dehydroepiandrosterone sulfate.