Trial Against INtractable Type 2 Diabetes (CAPTAIN-T2D)

CAPTAIN-T2D will take place in two parts. Part 1 (Screening) will evaluate patients with type 2 diabetes and elevated cortisol risk factors for trial eligibility and the presence of elevated cortisol. Participants deemed eligible from Part 1 will be randomized to either clofutriben or placebo in the double-blind (participant and investigator), dose-ranging, interventional Part 2 (Treatment).

Inclusion Criteria: * From Screening 1 * Age at least 18 years. * HbA1c ≥7.5% documented within 3 months prior to Screening 1. (The historical HbA1c value must have been obtained after at least 2 months on the current \[as of Screening 1\] regimen). * Treatment with stable and adequate doses of ≥2 injectable or oral ADMs. (An ADM will be deemed stable if the dose has been the same for at least 3 months prior to Screening 1 and without change between Screening 1 and Day 1) (An ADM dose will be deemed adequate if it is at or above the maximal labelled dose, or a sub-maximal, but not starting, dose if limited by tolerability (confer with MM if less than half-maximal dose). * Adequate total daily insulin is defined as at least 0.3 units/kg/day. Insulin dose will be deemed stable with adjustments of up to 20% total daily dose during the 3 months prior to Screening 1 or between Screening 1 and Day 1. * Use of insulin pumps or insulin brand changes (e.g., due to insurance change or shortage) are to be discussed with the MM. * At least one of the following * ≥3 stable and adequate ADMs; * diabetes complication (retinopathy, nephropathy, neuropathy, atherosclerotic heart disease); * hypertension requiring ≥2 adequately dosed AHMs; * adequately dosed basal or basal plus prandial insulin in addition to at least 1 other ADM; and * adequately dosed incretin agonist (a single or combination agent counts as one ADM) in addition to at least 1 other ADM; * evidence or history of osteoporosis or non-traumatic fracture (e.g., vertebral body compression); * or established diagnosis of a neoplastic (non-malignant) source of hypercortisolism and have failed, are ineligible for, or declined surgery. At DST • Post-DST cortisol level \>1.8 µg/dL and serum dexamethasone ≥140 ng/dL. Patients with an established diagnosis of neoplastic hypercortisolism do not require a DST. At Screening 2 * HbA1c ≥7.5% at Screening 2. At Day 1 * No change in, or initiation of, medications for hypertension within 1 month prior to Day 1. Exclusion Criteria: * New-onset diabetes (onset \15 min\] or repeated episodes of either Level 2 hypoglycemia leading to \>1%, or Level 1 hypoglycemia leading to \>4%, in "time below range" within 3 months prior to Screening 1 or between Screening 1 and Day 1). * Any of the following in medical history: * Type 1 diabetes mellitus (T1D), latent autoimmune diabetes in adults (LADA), or familial forms of maturity-onset diabetes of the young (MODY); * A hemoglobinopathy or other condition which may interfere with measurement of HbA1c (e.g., sickle cell disease HbSS or other variants HbEE thalassemia, hemolytic anemia, recent blood transfusion); * Hypersensitivity or severe reaction to dexamethasone; * Pheochromocytoma, or suspicion thereof; * Anorexia, or other eating disorder; * Glucocorticoid resistance; * Multiple sclerosis; * Significant hepatic impairment (e.g., Child-Pugh Class B or C); * Idiopathic thrombocytopenic purpura; * Untreated or inadequately controlled moderate-to-severe sleep apnea (apnea-hypopnea index ≥15). (Patients whose condition has been well controlled with Continuous Positive Airway Pressure (CPAP) use for at least 3 months prior to Screening 1 are not excluded. Patients with a STOP-BANG score 5-8 should be referred for a sleep study outside the trial and may rescreen if found not to have moderate-to-severe sleep apnea); * Current alcohol consumption \>14 units/week or \>4 units in a single day for males, or \>7 units/week or \>3 units in a single day for females. (Patients with a CAGE score 2-4 should be evaluated further outside the trial and may be rescreened if found not to have an alcohol \[or other substance\] use disorder); * Untreated or inadequately controlled major depressive disorder, generalized anxiety disorder, bipolar disorder, post-traumatic stress disorder, or schizophrenia.(Patients whose condition has been well controlled with stable medical therapy, or has been asymptomatic, for at least 3 months prior to Screening 1 are not excluded); or * Any other medical condition (including malignancy) that is likely to interfere with trial assessments or the patient's ability to complete the trial. * Any of the following in medication history: * Any of the excluded medications listed in Section 6.9; * Any investigational drug within 4 weeks or within less than five times the drug's half-life, whichever is longer, prior to Screening 1 or between Screening 1 and Day 1; * Woman of childbearing potential (WOCBP) not willing to adhere to highly effective contraception or strict abstinence for the duration of the trial and for 90 days post completion/discontinuation; and * Pregnancy (including a positive urine test) or current breast feeding. From Screening 2 • Prior probability of undiagnosed endogenous Cushing syndrome based on either of: * wo morning serum cortisol values after dexamethasone suppression \>5.0 mcg/dL together with plasma dexamethasone \>140 ng/mL; or * a morning serum cortisol value after dexamethasone suppression \>1.8 mcg/dL, together with plasma dexamethasone \>140 ng/mL and any one of the following that is not attributable to an etiology other than endogenous Cushing's syndrome: * supraclavicular/dorsocervical fat accumulation; * irounding of the face (especially compared with prior photos); * skin changes (violaceous striae, skin thinning, or excessive bruising); * proximal muscle weakness on exam; or * history of deep vein thrombosis/pulmonary embolism. * Plans for, or medically unable to forego, treatment for endogenous Cushing syndrome or ACS within the next 8 months. (For clarity, patients with EnCS or ACS, not having such treatment plans, and medically able to forego treatment for 8 months may enroll if otherwise eligible). * Severe, poorly controlled hypertension (mean systolic BP \>160 mmHg or mean diastolic BP \>100 mmHg) at Screening 2 or between Screening 2 and Day 1, including by at-home monitoring. (Such patients will be eligible to rescreen for Part 2 when they restore BP \1.5 × ULN.(excepting benign conditions such as Gilbert's) * Known hypersensitivity to clofutriben or to any of the product