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 Hypercortisolism in Patients with Difficult to Control Type 2 Diabetes Despite Receiving Standard-of-Care Therapies: Prevalence and Treatment with Korlym^® (Mifepristone) (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.

Correspondence to Dr Daniel Einhorn; [email protected]

STRENGTHS AND LIMITATIONS OF THIS STUDY

• This study uses the widely accepted tests for identifying patients with hypercortisolism, particularly hypercortisolism of adrenal origin: The dexamethasone suppression test with dexamethasone level in combination with adrenocorticotropic hormone, dehydroepiandrosterone sulfate and adrenal CT.

• The sample size is large enough to provide a robust assessment of hypercortisolism prevalence in a diverse study population with difficult-to-control type 2 diabetes (T2D).

• Part 2 of the study uses a randomised, placebo-controlled prospective design to test the efficacy of pharmacotherapy for hypercortisolism that directly antagonises the effect of cortisol.

• Limitations include not performing the historically standard confirmatory tests (late-night salivary cortisol and 24-hour urinary free cortisol) for hypercortisolism because they have been shown to lack sufficient sensitivity to rule out hypercortisolism due to autonomous adrenal hypersecretion of cortisol.

• The results may not be applicable to individuals with hypercortisolism who do not have T2D or to the broader population of people with T2D who do not have hypercortisolism.

Introduction

Impact of excess cortisol on type 2 diabetes

Glucocorticoids decrease insulin secretion, increase insulin resistance and have a negative impact on virtually every component of the metabolic defects that underlie type 2 diabetes (T2D).^{1 2} Specifically, excess cortisol contributes to metabolic dysfunction and negatively impacts glucose homoeostasis by causing a beta-cell defect that impairs insulin secretion and inhibits the insulinotropic effect of glucagon-like peptide 1.^3–6 Chronic excess cortisol activity pathologically disrupts insulin post-receptor signalling, thereby causing a form of insulin resistance.⁷ It is, therefore, not surprising that chronic excess cortisol activity, such as occurs in hypercortisolism, could contribute to a form of T2D that is difficult to control with standard therapies.

Hypercortisolism as a pathological condition

Endogenous hypercortisolism describes a spectrum of excess cortisol production of varying severity that occurs through several pathogenic mechanisms.^{8 9} Cushing disease, which results from excess pituitary adrenocorticotropic hormone (ACTH) production, often produces ‘classic’ Cushing syndrome, recognised by physical features that include moon facies, plethora, supraclavicular and dorsocervical fat pads, violaceous striae, proximal muscle wasting and central obesity.^{8 10 11}

Analogous to other endocrine organs that can pathologically secrete excess hormones, the adrenal glands can pathologically secrete excess cortisol in an autonomous fashion, much like primary hyperaldosteronism. This autonomous production leads to a type of endogenous hypercortisolism where individuals present with cortisol-related comorbidities, such as diabetes, hypertension, obesity, mood disturbances and/or fragility fractures but typically do not show classic physical features of Cushing syndrome.^{8 11 12} This type of hypercortisolism may be caused by an adrenal adenoma or hyperplasia, but occasionally no adrenal lesion is identified by routine CT scan.^{8 13}

Excess cortisol affects nearly every part of the body, meaning that hypercortisolism has a variable clinical presentation.^{10 11 14–16} While individuals with hypercortisolism of autonomous adrenal origin typically have less severe elevations in serum cortisol than those with Cushing disease, any degree of hypercortisolism may be associated with a constellation of adverse outcomes.^{8 11 12} For individuals with adrenal adenomas, hypercortisolism is usually a persistent disease; it neither progresses in severity nor resolves spontaneously¹⁵ and causes cumulative adverse consequences over time. In the long term, hypercortisolism is independently associated with cardiovascular disease and increased mortality.^{12 15 17–21} Individuals with hypercortisolism from adrenal incidentalomas have been shown to have a significantly greater risk of cardiovascular events versus those without hypercortisolism (OR 2.7, p=0.04).¹⁸ Moreover, individuals with hypercortisolism resulting from adenomas, versus those with non-secreting adenomas, have demonstrated a significantly higher rate of cardiovascular events (16.7% vs 6.7%, p=0.04), decreased cardiovascular-specific survival rate (78.4% vs 97.5%, p=0.02) and decreased overall survival rate (57.0% vs 91.2%, p=0.005).¹⁷ In addition, a meta-analysis identified a higher prevalence of new cardiovascular events for individuals with adenomas that produced cortisol versus those with non-secreting adenomas (15.5% vs 6.4%).¹⁵ Other studies have identified adverse cardiovascular changes, including increased left ventricular mass and increased carotid intima–media thickness, in individuals with hypercortisolism.^{19 20}

Diagnosing hypercortisolism

The 1-mg overnight dexamethasone suppression test (DST) with a morning plasma cortisol level of >1.8 µg/dL (50 nmol/L) is recognised as the most valuable and sensitive test for identifying hypercortisolism; it is recommended in the 2023 European Society of Endocrinology Clinical Practice Guideline on the management of adrenal incidentalomas,²² as well as in earlier guidelines and recommendations.^{10 23–26} In patients with adrenal adenoma, a morning plasma cortisol threshold level of >1.8 µg/dL with the 1-mg DST is correlated with increased morbidity and mortality.^{17 27} In contrast, urinary-free cortisol (UFC) and late-night salivary cortisol (LNSC) levels are not considered sufficiently sensitive to diagnose most cases of hypercortisolism of adrenal origin.^{9 10 23 24 26} Individuals with UFC levels defined as ‘normal’ may present with severe cortisol-driven comorbidities.^{11 28} UFC and LNSC also demonstrate high intraindividual variability.²³

To perform a DST, the individual is instructed to take a 1-mg oral dose of dexamethasone at approximately 23:00 hours, before undergoing a blood draw for plasma cortisol at approximately 8:00 hours the next day.¹⁰ A dexamethasone level is measured from the same blood sample if the cortisol level is >1.8 µg/dL, to confirm that the amount of dexamethasone ingested was adequate for suppression.²⁹

The >1.8 µg/dL cut-off point for the post-DST plasma cortisol level has shown good sensitivity and specificity for identifying patients with hypercortisolism of adrenal origin who are at risk for cardiovascular consequences.²⁴ Reduced ACTH and dehydroepiandrosterone sulfate (DHEAS) levels support the diagnosis of hypercortisolism of adrenal origin.^{8 12 22 24 25} It is known that not all patients with hypercortisolism due to autonomous adrenal function have discernible nodules or other adrenal abnormalities on CT scan. Historically, the adrenal nodule was frequently found first, which then leads to a workup for hypercortisolism. In the 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) study being introduced here, difficult-to-control T2D as a potential cardiometabolic manifestation of hypercortisolism is found first, which then leads to the workup for hypercortisolism. In either case, the 1-mg DST with dexamethasone level is a sensitive and specific first-line test. In the CATALYST population, what percentage will turn out to have nodules on CT is an important endpoint. Part 2 will demonstrate whether therapy for hypercortisolism benefits patients regardless of the presence of a nodule(s). This would be akin to what is understood for hyperaldosteronism.

Prevalence of hypercortisolism

Owing to its heterogeneous clinical presentation and the diverse diagnostic methods, hypercortisolism can be overlooked clinically and its prevalence in the United States is unknown. When diagnosed with the 1-mg DST threshold cortisol level of >1.8 µg/dL, hypercortisolism without overt signs and symptoms of Cushing syndrome has been identified in 45% of individuals with adrenal incidentalomas in a multicentre study.²⁸ Certain populations have an increased risk for hypercortisolism, including those with T2D, arterial hypertension and osteoporosis.¹¹ In T2D, prevalence estimates of hypercortisolism vary widely, depending on testing methods used, the population studied and the severity of the T2D. The prevalence of hypercortisolism in difficult-to-control T2D is not established. Studies use different definitions for hypercortisolism and poorly controlled T2D, do not usually distinguish between hypercortisolism and Cushing disease and are limited by small population sizes and variable testing methodologies. Using methods where tests in addition to the DST are required, hypercortisolism prevalence as high as 10.2% has been reported; using DST alone, as is becoming the standard, the prevalence is estimated to be closer to 20%.^{13 30 31} A more complete understanding of the prevalence of hypercortisolism in people with difficult-to-control T2D is needed.

Treating hypercortisolism

The current standard of care for treating individuals with hypercortisolism of adrenal origin is adrenalectomy when a single adenoma is the source, the risk–benefit ratio for the patient is favourable, and the patient is in agreement. Where surgery is not feasible, the default approach is to optimise the management of comorbidities such as T2D, hypertension and hyperlipidaemia. However, pharmacological treatment of comorbidities without treating the hypercortisolism does not reduce risks for future cardiovascular morbidities and mortality.¹² This paradigm is analogous to the need to treat hyperaldosteronism with antialdosterone therapy (ie, surgery or an aldosterone antagonist) to protect the affected individual from the inflammatory and cardiovascular effects of the aldosterone.^{32 33}

Petramala et al ¹² demonstrated the inadequacy of treating comorbidities and not using therapy to directly lower the effect of cortisol in individuals with hypercortisolism resulting from adrenal incidentalomas. They compared three groups: (1) those with hypercortisolism whose comorbidities (eg, T2D, hypertension) were well treated medically without addressing the underlying hypercortisolism; (2) those with hypercortisolism who had surgical removal of the adrenal adenoma, and therefore, removal of the excess cortisol and (3) those without hypercortisolism who had non-secreting adrenal adenomas. Those individuals who received medical treatment only for their comorbidities experienced significantly more cardiovascular events compared with those who had surgical adenoma removal (unadjusted risk ratio (RR) 2.10, p<0.001), and to those who did not have hypercortisolism (unadjusted RR 2.56; figure 1A). Over a 15-year period, the group with comorbidities treated medically without therapy to lower the effect of cortisol experienced a nearly twofold increase in cardiovascular mortality compared with the surgically treated group (unadjusted RR 1.72, p<0.001; figure 1B). These results demonstrated that excellent management of comorbidities is not sufficient to protect individuals from the increased cardiovascular morbidity and mortality associated with hypercortisolism, and that treating the underlying excess cortisol is also necessary. Furthermore, even those who had surgical removal of the adenoma had significantly reduced survival compared with those with non-functioning adenomas.¹² Therefore, any length of time with hypercortisolism appears to negatively impact survival, and earlier treatment of hypercortisolism would likely confer more favourable long-term outcomes. Similarly, in a prospective, randomised clinical trial comparing surgical removal of cortisol-secreting adenomas (removing cortisol excess) to medical therapy of comorbidities (persistent excess cortisol), improvements in T2D and hypertension were significantly greater in the surgical group.³⁴ While these studies used surgery to address the underlying excess cortisol, the results might be extrapolated to pharmacological therapy that accomplishes a similar lowering of cortisol effect.

Figure 1. Cardiovascular events and survival in a study of patients with adrenal incidentalomas. 12 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 12 and reproduced with permission. MSH, pharmacological treatment for subclinical hypercortisolism; NFA, non-functional adrenal adenoma; RR, risk ratio; SSH, surgical treatment for subclinical hypercortisolism.

While minimally invasive adrenalectomy is the standard of care for adrenal adenomas causing hypercortisolism, surgery is not always possible.^{22 24 35} Notably, Petramala et al ¹² found that 75% of people with hypercortisolism resulting from adrenal incidentalomas either refused surgery or were not candidates for it based on diagnostic ambiguities, such as whether there was evidence of bilateral disease.

Pharmacotherapy may offer an alternative approach for addressing the underlying hypercortisolism in individuals who are not surgical candidates, or who have failed or refused surgery. Oral pharmacotherapy options in the USA for ACTH-independent Cushing syndrome include ketoconazole, levoketoconazole, metyrapone and mifepristone (Korlym^®, Corcept Therapeutics, Incorporated).^{9 35} Mifepristone is the only agent approved by the US Food and Drug Administration (FDA) for the treatment of hyperglycaemia secondary to endogenous Cushing syndrome in adults with T2D or impaired glucose tolerance who have failed or are not candidates for surgery (based on the pivotal SEISMIC trial).^35–37 Levoketoconazole is indicated for the treatment of endogenous hypercortisolaemia in patients with Cushing syndrome.³⁸ Metyrapone is approved as a diagnostic agent.³⁹ Ketoconazole has been used for Cushing syndrome off-label, but has potential for liver toxicity.⁴⁰ Studies of these agents in hypercortisolism without overt Cushing syndrome are limited. Furthermore, ketoconazole, levoketoconazole and metyrapone act by inhibiting cortisol production and lowering UFC,³⁵ which may not be elevated in these patients. Of these agents, only mifepristone antagonises cortisol activity directly at the glucocorticoid receptor, which may be a more appropriate mechanism in this population with often normal UFC.

Mifepristone is a competitive antagonist of the progesterone and glucocorticoid receptors. Because mifepristone acts at the receptor level to competitively antagonise the effects of cortisol, circulating levels of cortisol and ACTH do not decrease with mifepristone treatment and are not measured to monitor therapy. For hypercortisolism in individuals with adrenal adenomas, pilot studies of mifepristone have suggested benefit, such as improvements in plasma glucose and insulin resistance.^{21 41}

The CATALYST trial: methods and analysis

Overview

CATALYST (NCT05772169) is a phase 4, two-part, multicentre trial in the USA that is designed to answer several of the questions raised above. The aim of part 1 is to determine the prevalence of hypercortisolism (based on post-DST cortisol level >1.8 µg/dL, with dexamethasone level ≥140 ng/dL) in the largest population ever studied of patients with difficult-to-control T2D (haemoglobin A1c (HbA1c) 7.5%–11.5% despite multiple standard-of-care therapies). It also serves to identify patients who may qualify to enrol in part 2. Part 2 assesses the safety and efficacy of mifepristone to lower HbA1c compared with placebo in individuals identified in part 1 with difficult-to-control T2D and hypercortisolism who do not require further assessment for elevated ACTH and are not candidates for, or decided against, surgery.

CATALYST is enrolling individuals with difficult-to-control T2D, a population with important unmet medical needs and a higher prevalence of hypercortisolism than the general diabetes population based on smaller studies conducted outside the USA.^{11 30 42 43} A large meta-analysis suggested that hypercortisolism is 1.9–3.5 times more common in individuals with T2D who require insulin treatment and/or have hypertension or diabetic complications than those without these factors.⁴³ Prevalence data from CATALYST may be helpful in determining whether patients with difficult-to-control T2D should be screened for hypercortisolism in clinical practice.^{11 43}

Study design

CATALYST is a two-part, multicentre trial being conducted at approximately 30 sites in the USA. Part 1 is a non-interventional trial and part 2 is an interventional, prospective, double-blind, placebo-controlled, randomised clinical trial (figure 2). Randomisation in part 2 is stratified by the presence or absence of an abnormal adrenal CT scan. Recruitment began on 31 March 2023 and was completed on 26 April 2024.

Figure 2. Study schema and patient flow for CATALYST. ACTH, adrenocorticotropic hormone; APRI, aspartate aminotransferase-to-platelet-ratio index; CATALYST, 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); DHEAS, dehydroepiandrosterone sulfate; DST, dexamethasone suppression test; FIB-4, fibrosis-4; HbA1c, haemoglobin A1c; T2D, type 2 diabetes.

Study participants

The key eligibility criteria for parts 1 and 2 are detailed in tables 1 and 2. Participants identified in part 1 to have hypercortisolism (post-DST cortisol >1.8 µg/dL and dexamethasone ≥140 ng/dL) with ACTH≤15 pg/dL or 15–30 pg/dL with DHEAS≤100 µg/dL for those with abnormal adrenal CT scan, and ACTH and DHEAS in the normal range for those with normal adrenal CT scan, may enrol in part 2. Participants suspected of having elevated ACTH are referred for further diagnostic evaluation and treatment outside the study. Participants with surgically amenable disease are given the option to undergo surgery outside the study. Participants are required to consent separately for the two study parts. Part 1 is designed to minimise obstacles for participants to take part in the assessment of prevalence without committing to an intervention trial while part 2 is designed to adhere strictly to the FDA-approved labelling for mifepristone.³⁶

Table 1

Key eligibility criteria for CATALYST part 1

Inclusion criteria	Exclusion criteria
Part 1
Age 18–80 years. Difficult-to-control T2D with diagnosis ≥1 year prior defined as: HbA1c 7.5%–11.5% AND ≥3 antihyperglycaemic drugs OR Insulin plus any other antihyperglycaemic drugs OR ≥2 antihyperglycaemic drugs AND (a) the presence of ≥1 diabetes complication (eg, retinopathy, diabetic nephropathy and chronic kidney disease (eGFR<60 mL/min/1.73 m2), diabetic neuropathy, atherosclerotic heart disease with diabetes) AND/OR (b) concomitant hypertension requiring ≥2 antihypertension medications. Women on oral contraceptive pills (OCPs) may be screened but must be willing and able to stop OCPs for at least 3 weeks prior to DST.	Type 1 diabetes mellitus. New-onset diabetes less than 1 year. Systemic glucocorticoid medication exposure within 3 months (excluding inhalers or topical). Pregnancy or lactation. For women of childbearing potential (all women <50 years old, women whose surgical sterilisation was performed <6 months ago, and women who have had a menstrual period in the last 12 months), have a positive pregnancy test before dexamethasone administration. Haemodialysis or end-stage renal disease. Severe untreated sleep apnoea. Excessive alcohol consumption (>14 units/week for male, >7 units/week for female). Severe medical, surgical or psychiatric illness. Night shift worker (awake from 23:00 to 7:00 hours). Has taken any investigational drug within 4 weeks prior to screening, or within less than five times the drug’s half-life, whichever is longer. Diagnosed with or having treatment plans for Cushing syndrome using any of the following treatments: mifepristone, metyrapone, osilodrostat, ketoconazole, fluconazole, aminoglutethimide, etomidate, octreotide, larazotide, pasireotide, long-acting octreotide or pasireotide. History of hypersensitivity or severe reaction to dexamethasone.

CATALYST, 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); DST, dexamethasone suppression test; eGFR, estimated glomerular filtration rate; HbA1c, haemoglobin A1c; T2D, type 2 diabetes.

Table 2

Key eligibility criteria for CATALYST part 2

Inclusion criteria	Exclusion criteria
Part 2
Completed part 1 with post-DST cortisol level of >1.8 µg/dL, dexamethasone level ≥140 ng/dL. No change in, or initiation of, diabetes medications within 4 weeks prior to first study drug dose.	Any change in status of exclusion criteria from part 1. Requires inhaled glucocorticoid use and may require systemic glucocorticoids if their condition deteriorates during study. Severe, poorly controlled hypertension at screening (defined as mean systolic BP>160 mm Hg or mean diastolic BP>100 mm Hg); must be able to correct to a BP of <160/100 mm Hg before first dose of study drug. Refractory hypokalaemia that cannot be corrected; must be able to correct to potassium level of ≥4.0 mEq/L before first dose of study drug. Poorly controlled hyperthyroidism/hypothyroidism (confirmed by TSH or free thyroxine). Plans for adrenalectomy or adrenal nodulectomy. Renal insufficiency (eGFR<30 mL/min/1.73 m2). Liver enzymes >3 times ULN (ALT or AST) or bilirubin >1.5 times ULN. Taking drugs metabolised by CYP3A and CYP3A substrates with narrow therapeutic ranges. Systemic corticosteroid use. Pregnancy or lactation. For women of childbearing potential (all women <50 years, women whose surgical sterilisation was performed <6 months ago, and women who have had a menstrual period in the last 12 months), have a positive pregnancy test before treatment. Hormonal contraceptive use. History of unexplained vaginal bleeding, endometrial hyperplasia with atypia or endometrial carcinoma. Known hypersensitivity to mifepristone or to any of the product components

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; CATALYST, 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; DST, dexamethasone suppression test; eGFR, estimated glomerular filtration rate; TSH, thyroid-stimulating hormone; ULN, upper limit of normal.

Study endpoints

The primary endpoint of part 1 is the percentage of participants with hypercortisolism, defined as a post 1-mg DST serum cortisol level >1.8 µg/dL and dexamethasone level ≥140 ng/dL, among patients with difficult-to-control T2D despite receiving standard-of-care therapies. Change in HbA1c from baseline to week 24 in participants with hypercortisolism with and without abnormal adrenal CT scan, treated with mifepristone versus placebo, is the primary endpoint of part 2. Safety is also being assessed in part 2.

Secondary endpoints in part 1 include assessment of clinical characteristics that increase the likelihood of a patient having hypercortisolism and the percentage and clinical/laboratory characteristics of participants with hypercortisolism with and without abnormal adrenal CT scan. The percentage and clinical/laboratory characteristics of participants with difficult-to-control T2D who have a post-DST cortisol level of 1.2–1.8 µg/dL and whether subsets of white blood cells on a complete blood count are different in patients with hypercortisolism compared with those with labs in the normal range will be assessed in exploratory endpoints.

Secondary endpoints in part 2 include changes in antidiabetes and antihypertension medications from baseline to week 24 for mifepristone and placebo, as well as changes in body weight, body mass index, waist circumference, glycaemic metrics (eg, fasting blood glucose, reduction in insulin or sulfonylurea doses), blood pressure, lipids (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides), quality of life, fibrosis-4 and aspartate aminotransferase-to-platelet-ratio index.

Treatment in part 2

In part 2, participants are randomised 2:1 to treatment with mifepristone or matched placebo. Participants begin with 300 mg once daily with food and, assuming good tolerability, advance to 600 mg once daily at week 4. They may remain on this dose for the 24 weeks of the study. At the discretion of the investigator, the dose can be increased to 900 mg once daily at week eight or 12.

Participants are required to have serum potassium ≥4.0 mEq/L before initiating study drug, to reduce the risk of hypokalaemia due to cortisol-induced mineralocorticoid receptor stimulation. Serum potassium is checked 2 weeks after study drug initiation and 2 weeks after every dose escalation. Once the dose of study drug is stabilised, potassium may be checked every 4 weeks. If the potassium concentration falls to <4.0 mEq/L, consideration is given to initiating or increasing the dose of a mineralocorticoid receptor antagonist or a potassium-sparing diuretic.

Mifepristone may lead to hypoglycaemia in individuals taking insulin or sulfonylureas. To avoid this, self-monitored blood glucose (SMBG) levels are followed closely and insulin and sulfonylurea doses lowered as needed. While the protocol provides for rescue therapy for hypoglycaemia and hyperglycaemia, it is intended that diabetes medications that do not produce hypoglycaemia will not be reduced during the 24-week treatment phase. Safe T2D management is at the discretion of the investigator, with diabetes medication initiation or intensification permitted and carefully documented.

The dose of study drug may be reduced for tolerability issues and interrupted or modified for symptoms of cortisol withdrawal or significant trauma, medical illness or surgery. Study participation is permanently discontinued at the investigator’s discretion, for malignancy or other severe medical condition, or for pregnancy.

Procedures

The schedule of study procedures for part 1 and part 2 are shown in tables 3 and 4, respectively. On completion of demographics, a complete medical and surgical history including comorbidities and medications, a limited physical examination for blood pressure, weight, waist circumference, height and physical characteristics of a Cushingoid appearance, and a negative urine pregnancy test (in women of childbearing potential), participants undergo the 1-mg DST (figure 3). The serum dexamethasone level is measured whenever post-DST serum cortisol level is >1.8 µg/dL. If the serum cortisol level is >1.8 µg/dL and the dexamethasone level is ≥140 ng/dL, the participant has an additional fasting morning blood draw at the next visit for ACTH, DHEAS, cortisol, HbA1c, chemistry panel, thyroid-stimulating hormone, lipids and complete blood count. Non-contrast CT imaging of the adrenal glands is also to be performed and will be read locally as well as centrally and blinded by The Mayo Clinic adrenal radiologist. If the serum cortisol level with the DST is >1.8 µg/dL but the dexamethasone level is <140 ng/dL, the DST can be repeated with 4 mg dexamethasone.

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

Table 3

Schedule of study procedures—part 1 (prevalence phase)

Study procedure	Visit 1: screening (up to 6 weeks)	Visit 1 a: DST	Visit 2: If cortisol >1.8 µg/dL and dexamethasone ≥140 ng/dL
Informed consent for part 1	x
Inclusion/exclusion criteria	x
Demographics	x
Medical and medication history	x
Limited physical examination*	x
Blood pressure	x
HbA1c	x		x
Urine pregnancy test†	x
AM cortisol and reflex dexamethasone level‡		x
Serum chemistry§			x
Haematology (CBC and differential)			x
Lipid panel¶			x
ACTH			x
DHEAS			x
Cortisol			x
TSH			x
Correct potassium as needed			x
Schedule adrenal CT			x
STOP-BANG and CAGE questionnaires			x
Adverse events**	x		x
Concomitant medications			x
Discuss participation in part 2			x

*Height, weight, waist circumference and limited assessment of bodily characteristics of a Cushingoid appearance (eg, facial rubor, moon facies, dorsocervical fat pad, supraclavicular fat pad and striae).

†Pregnancy tests for women of childbearing potential. If urine pregnancy is positive, the result should be confirmed with serum pregnancy test. Must be negative to schedule DST.

‡Cortisol and reflex dexamethasone level to be performed at 8:00 hours the morning after taking the dexamethasone dose at approximately 23:00 hours. Dexamethasone level checked only in those patients whose cortisol is >1.8 µg/dL. Option to repeat DST using 4 mg dose and repeating dexamethasone level to assure it is ≥140 ng/dL. If dexamethasone level does not reach ≥140 ng/dL, the patient is referred out of the study.

§Full chemistry profile that includes albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood urea nitrogen, calcium, chloride, creatinine, glucose, lactate dehydrogenase, magnesium, phosphorus, potassium, sodium, creatine kinase, total and direct bilirubin, total protein, uric acid.

¶Total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, very low-density lipoprotein cholesterol and triglycerides.

**Adverse events will be collected after the informed consent form is signed.

ACTH, adrenocorticotropic hormone; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; DHEAS, dehydroepiandrosterone sulfate; DST, dexamethasone suppression test; HbA1c, haemoglobin A1c; TSH, thyroid-stimulating hormone.

Table 4

Schedule of study procedures—part 2 (treatment phase)

Study procedure	Baseline	Double-blind, placebo-controlled Weeks 1–18			Closing visit or early termination	Follow-up visit*
Visit day/week	Day 1	Weeks 2 and 6	Weeks 4, 8 and 18	Week 12	Week 24	Week 28+
12-Lead ECG	x
Limited physical examination			x	x	x	x
Blood pressure	x		x	x	x	x
Patient education†	x	x	x	x
Basic metabolic profile‡		x	x
Serum chemistry§				x	x	x
Haematology (CBC and differential)					x
Lipid panel¶				x	x
HbA1c				x	x
TSH				x	x
Correct potassium as needed		x	x	x	x	x
Review patient SMBG	x	x	x	x	x	x
Pregnancy test**	x	x	x	x	x	x
WHO-5 Well-Being Index, CushingQOL and DIDP questionnaires, 1-MSTST	x				x
Adverse events	x	x	x	x	x	x
Concomitant medications	x	x	x	x	x	x
Dosing diary	x	x	x	x	x
Study drug dispensing and/or adherence	x	x	x††	x††	x‡‡

*The follow-up visit will occur 30 days (window of +7 days) after the last dose of study drug.

†Patient education regarding potential side effects of mifepristone including steroid withdrawal symptoms, hypoglycaemia and hypokalaemia. Plans to mitigate those side effects will be reviewed such as treatment for nausea, arthralgias or myalgias, or headache.

‡Sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine.

§Full chemistry profile that includes albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood urea nitrogen, calcium, chloride, creatinine, glucose, lactate dehydrogenase, magnesium, phosphorus, potassium, sodium, creatine kinase, total and direct bilirubin, total protein, uric acid.

¶Total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, very low-density lipoprotein cholesterol and triglycerides.

**Pregnancy tests for women of childbearing potential. At all study visits, pregnancy test will be a urine test; if urine pregnancy test is positive, the result should be confirmed with serum pregnancy test.

††Escalate study drug dose to mifepristone 600 mg once daily or placebo on week 4 (assuming the patient has tolerated the 300 mg daily dose). Optional dose escalation to mifepristone 900 mg once daily or placebo on week 8 or week 12 (assuming the patient has tolerated the 600 mg daily dose). If the dose is increased to 900 mg once daily, a follow-up visit within 2 weeks is necessary to monitor the effect on SMBG and potassium. This follow-up visit follows the same procedures and assessments as the week 2 visit.

‡‡At the Closing/Early Termination Visit, only study drug adherence will be performed. All remaining study drug will be collected, and no further study drug will be dispensed.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; CGM, continuous glucose monitoring; CushingQOL, Cushing Disease Quality of Life instrument; DIDP, Diabetes Attitudes, Wishes, and Needs Impact of Diabetes Profile; HbA1c, haemoglobin A1c; 1-MSTST, One Minute Sit-to-Stand Test; SMBG, self-monitored blood glucose; TSH, thyroid-stimulating hormone; WHO-5 Well-Being Index, World Health Organization-5 Well-Being Index.

In part 2, participants undergo a 12-lead ECG, blood pressure measurement and urine pregnancy test (women of childbearing potential). Quality of life assessments are scheduled at baseline and end of the study.

Blood pressure and a limited physical examination are repeated at weeks 4, 8, 12, 18 and 24 or at early termination, and at a single follow-up visit (week 28). The basic metabolic panel or serum chemistry with potassium check and correction is repeated at each visit along with a urine pregnancy test (women of childbearing potential). Haematology assessments are to be repeated at the end of the study. The HbA1c and lipid panel are also scheduled to be repeated at week 12 and end of the study, along with thyroid-stimulating hormone.

Participants must perform appropriate SMBG and report the results at each visit. The frequency of SMBG needed varies among participants, especially those who do not take insulin or sulfonylureas. The frequency and type of SMBG is at the discretion of the investigator.

Adverse event assessment occurs throughout the study and will continue for 30 days following the last dose. Adverse event severity is categorised using the Medical Dictionary for Regulatory Activities and graded according to the Common Terminology Criteria for Adverse Events V.5.0.

Sample size calculation

For part 1, the planned screening sample size is approximately 1000 participants, which, based on current prevalence estimates, should identify enough participants for enrolment in part 2. The protocol states that enrolment may be ended early if there are sufficient data to complete Part 1 and to enrol a sufficient number of participants to complete part 2. In part 2, approximately 114 participants will be randomised 2:1 to mifepristone or placebo. Assuming a target difference between treatment arms of 1.5% in change from baseline to week 24 in HbA1c with SD of 1.5%, setting a type I error rate (α) at 0.05 and a 20% discontinuation rate, this ensures 90% power to detect a significant difference between groups.

Statistical analysis

All enrolled participants who consent, meet study eligibility criteria and complete the DST, are being analysed for the primary endpoint in part 1; patients with hypercortisolism as well as patients with hypercortisolism with or without abnormal CT scan will be analysed for the secondary endpoints in part 1. In part 2, the intention-to-treat population (all patients randomised) is assessed for the primary and secondary endpoints. Safety is being analysed in all participants who receive at least one dose of study treatment in part 2. In part 1, no hypothesis testing is being carried out. The proportion of participants with hypercortisolism will be reported with the 95% CI. In general, continuous endpoints will be summarised using descriptive statistics, and categorical endpoints using the number and percentages of patients in each category. In part 2, the null hypothesis of no difference between groups in HbA1c at week 24 is tested using a two-sided test at 0.05 level of significance. A mixed model for repeated measurements (MMRM) analysis will be used for the analysis of the primary endpoint. The model will include treatment as a main effect; baseline HbA1c and stratification factor (at randomisation) will be included as covariates. All continuous endpoints will be analysed using a similar MMRM model. All binary endpoints will be analysed with a Cochran-Mantel-Haenszel test that includes treatment and the stratification factor at randomisation. For all analyses, a pooling of strata will be considered if any stratum contains fewer than five patients.

Ethics and dissemination

This study is being conducted in accordance with ethical review committees and/or local regulations. The protocol and all pertinent materials have been approved by the following institutional review boards (IRBs): Cleveland Clinic IRB (Cleveland, Ohio, USA) and Advarra IRB (Columbia, Maryland, USA). The study is being performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and is consistent with International Conference on Harmonisation Guidelines for Good Clinical Practice and applicable regulatory requirements. Written informed consent is being obtained from all participants.

The authors thank Laura Evans, PharmD, and Holly Strausbaugh, PhD, of Twist Medical for assistance with manuscript preparation and editing that was funded by Corcept Therapeutics. Additional editorial assistance was provided by Tina K. Schlafly, PhD, CMPP, of Corcept Therapeutics.

Data availability statement

Upon study completion, results will be presented at relevant scientific congresses and published in peer-reviewed journals. De-identified datasets for the results reported in such publications may be made available to qualified researchers following submission of a methodologically sound proposal to [email protected]. Data will be made available for such requests following the online publication of the related article and for 1 year thereafter in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization. Data will be provided by Corcept Therapeutics Inc.

Ethics statements

Patient consent for publication

Not applicable.

Footnote

Contributors Study concept and design: RAD, JPF, RJA, IB, JBB, JWF, VAF, OH, YH, JR, ICT, AGM and DE. Recruitment of participants: JPF, LB, RSB, JBB, VAF, YH and JR. Investigation review: LB and JWF. Acquisition of data: JPF, LB, JBB, VAF, YH, JR and ICT. Data analysis: ICT. Record keeping: LB. Drafting of the manuscript: JWF, AGM and DE. Critical review of the manuscript: RAD, JPF, RJA, IB, LB, JBB, VAF, OH, YH, REP, JR, ICT, AGM and DE. All authors revised and approved the final version of the manuscript and agree to be accountable for all aspects of the work.

Funding This work was supported by Corcept Therapeutics.

Competing interests RAF reports: advisory board with AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Intarcia, Renalytix, Corcept Therapeutics; research support from Boehringer Ingelheim, AstraZeneca; speaker's bureau with AstraZeneca. RJA reports: research support from Neurocrine Biosciences and Diurnal, Spruce Biosciences, Corcept Therapeutics, Sparrow Pharmaceuticals; consulting fees from Quest Diagnostics, Corcept Therapeutics, Xeris Pharmaceuticals, Crinetics Pharmaceuticals, Adrenas Therapeutics, PhaseBio Pharmaceuticals, Novo Nordisk, Recordati Rare Diseases, H Lundbeck A/S, OMass Therapeutics, Sparrow Pharmaceuticals. IB reports: consulting and/or advisory board with Corcept, HRA Pharma, Recordati, Sparrow, Neurocrine, Diurnal, Spruce; data safety monitoring board with Adrenas; funding for investigator initiated award from Recordati. LB reports: contracted fees paid to the Ochsner Clinic Foundation by Novo Nordisk for consulting work, and to Corcept Therapeutics for both speaking and consulting services. RSB reports: grant funding from Corcept pharmaceuticals; research funding from Novo, Lilly and Novartis; and speaker bureaus for Novo, Lilly, AstraZeneca, Amgen,and Bayer. JBB reports: contracted fees and travel support for contracted activities for consulting work paid to the University of North Carolina by Novo Nordisk; grant support from Dexcom, Insulet, NovaTarg, Novo Nordisk, Sanofi, Tolerion and vTv Therapeutics; personal compensation for consultation from Alkahest, Altimmune, Anji, AstraZeneca, Bayer, Biomea Fusion, Boehringer Ingelheim, CeQur, Cirius Therapeutics, Corcept Therapeutics, Eli Lilly, Fortress Biotech, GentiBio, Glycadia, Glyscend, Janssen, MannKind, Medtronic, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego, Sanofi, Stability Health, Terns, Valo and Zealand Pharma; stock/options in Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio, Praetego, Stability Health. JWF reports: consultant and investigator for Corcept, Recordati. VAF reports: research support (to Tulane): grants from Fractyl, Jaguar Gene Therapy, Corcept; honoraria for consulting and lectures from Asahi, Bayer, Abbott, Boehringer Ingelheim, Corcept; stock options in Mellitus Health, BRAVO4Health; stock in Amgen, Abbott; patents pending for 1) BRAVO risk engine for predicting diabetes complications, 2) PAX4 gene therapy for type 1 diabetes. JPF reports: research support from Akero, Altimmune, Boehringer Ingelheim, 89bio, Eli Lilly, Intercept, IONIS, Janssen, Madrigal, Merck, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Sanofi, Shionogi, Corcept Therapeutics; advisory boards and consulting with Akero, Altimmune, Boehringer Ingelheim, Carmot Therapeutics, Echosens, 89bio, Eli Lilly, Gilead, Intercept, Merck, Novo Nordisk, Pfizer, Sanofi, Sun Pharma; speaker’s bureau with Eli Lilly; employment and stock ownership in Biomea Fusion. OH reports: scientific advisory board participation with Corcept Therapeutics, Strongbridge Pharma, Recordati Rare Diseases, Amryt Pharma, Neurocrine Biosciences, Lantheus, Xeris. YH reports: research grant from Amgen, Applied Therapeutic, Corcept, Ionis, Lilly, Merck, Regor; advisory/consultant role with Amgen, Applied Therapeutic, AZ, Bayer, BI, Corcept, Esperion, Mankind Pharma, Merck, Merck-Pfizer, Novartis, Novo Nordisk, Sanofi; speaker’s bureau with Bayer, Esperion, Novo Nordisk. REP reports: consulting fees from Bayer AG, Corcept Therapeutics Incorporated, Dexcom, Hanmi Pharmaceutical Co., Merck, Novo Nordisk, Pfizer, Sanofi, Scohia Pharma, Sun Pharmaceutical Industries; grants/research support from Hanmi Pharmaceutical Co., Janssen, Metavention, Novo Nordisk, Poxel SA, Sanofi. All funds are paid directly to REP’s employer, AdventHealth, a non-profit organisation that supports education and research. JR reports: advisory panels with Applied Therapeutics, Boehringer Ingelheim, Eli Lilly and Company, Hanmi, Intarcia, Novo Nordisk, Oramed, Sanofi, Scholar Rock, Structure Therapeutics, Terns Pharma and Zealand; research support from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Novartis, Intarcia, Merck, Novo Nordisk, Oramed, Pfizer, Sanofi. ICT, AGM and DE report: employed by and own stock in Corcept Therapeutics.

Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

Provenance and peer review Not commissioned; externally peer reviewed.

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