Study to Determine the Prevalence of Hypercortisolism in Patients With Type 2 Diabetes and Treatment With Korlym® (Mifepristone) (CATALYST)

This is a Phase 4 study with 2 parts at approximately 30 sites in the United States (US).

Part 1 (Prevalence Phase) is non-interventional and will assess the prevalence of hypercortisolism in a population with difficult to control T2D (HbA1c ≥7.5%) despite receiving standard-of-care therapies.

Patients from Part 1 Prevalence Phase who meet eligibility requirements can then enroll in Part 2 and will be randomized 2:1 to receive mifepristone or placebo once daily with food. Randomization will be stratified by presence of adenoma (yes/no).

Part 2 (Treatment Phase) is a randomized, prospective, placebo-controlled, double-blind multi-center trial that will assess the safety and efficacy of mifepristone treatment in patients with hypercortisolism who have difficult to control T2D despite receiving standard of care therapies.

For Part 1:

Inclusion criteria

Has difficult to control T2D (HbA1c ≥7.5% and ≤11.5%) based on HbA1c performed at screening.

AND Taking 3 or more anti-hyperglycemic drugs. OR Taking insulin and other anti-hyperglycemic drugs. OR Taking 2 or more anti-hyperglycemic drugs AND a.) the presence of 1 or more micro-vascular or macro-vascular complication (retinopathy, diabetic nephropathy and chronic kidney disease, diabetic neuropathy, atherosclerotic heart disease with diabetes); AND/OR b.) concomitant hypertension requiring 2 or more anti-hypertension 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 the dexamethasone suppression test.

Exclusion criteria

• Has type 1 diabetes mellitus.
• New-onset diabetes less than 1 year.
• Systemic glucocorticoid medications exposure (excluding inhalers or topical) within 3 months of screening.
• Is pregnant or lactating. For women of childbearing potential, have a positive pregnancy test before dexamethasone administration. A woman of childbearing potential includes all women <50 years old, women whose surgical sterilization was performed <6 months ago, and women who have had a menstrual period in the last 12 months.
• On hemodialysis or has end-stage renal disease.
• Has severe untreated sleep apnea as judged by the Investigator.
• Has excessive alcohol consumption (>14 units/week for male, >7 units/week for female) as judged by the Investigator.
• Has severe psychiatric illness by history (such as schizophrenia or dementia) as judged by the Investigator.
• Has severe medical or surgical illness as judged by the Investigator.
• Is a night shift worker, i.e., is awake from approximately 11 PM to 7 AM.
• Has taken any investigational drug within 4 weeks prior to screening, or within less than 5 times the drug's half-life, whichever is longer.
• Has had the diagnosis of Cushing syndrome or has used or plans to use any of the following treatments for Cushing syndrome:

• Mifepristone, metyrapone, osilodrostat, ketoconazole, fluconazole, aminoglutethimide, etomidate, octreotide, larazotide, pasireotide, long-acting octreotide or pasireotide.
• Has a history of hypersensitivity or severe reaction to dexamethasone

For Part 2:

Inclusion criteria

• Has completed Part 1 of the study with post-DST cortisol level of >1.8 μg/dL and dexamethasone level ≥140 ng/dL
• Will have no change in, or initiation of, diabetes medications within 4 weeks prior to first study drug dose

Exclusion criteria

• Has 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
• Has severe, poorly controlled hypertension at screening (defined as mean systolic BP >160 mmHg or mean diastolic BP >100 mmHg); must be able to correct to a BP of <160/100 mmHg before first dose of study drug
• Has refractory hypokalemia; must be able to correct to potassium level of ≥4.0 mEq/L before first dose of study drug
• Has poorly controlled hyperthyroidism/hypothyroidism before first dose of study drug (confirmed by TSH or free thyroxine)
• Has plans for adrenalectomy or adrenal nodulectomy
• Has renal insufficiency (eGFR <30 mL/min/1.73m2)
• Has liver test results >3x ULN (ALT or AST) or bilirubin >1.5x ULN
• Takes drugs metabolized by CYP3A and CYP3A substrates with narrow therapeutic ranges
• Receiving systemic corticosteroids that cannot be discontinued
• Uses hormonal contraceptives
• Has a history of unexplained vaginal bleeding, endometrial hyperplasia with atypia, or endometrial carcinoma
• Is pregnant or lactating
• Has a known hypersensitivity to mifepristone or any of the product components