Clofutriben for type 2 diabetes that is hard to control, with high cortisol

Who can take part

• 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

Who cannot take part

• Evidence for significant hypoglycemia while on their current diabetic treatment regimen(This includes episodes of symptomatic Level 3 hypoglycemia requiring external assistance for recovery, or CGM-documented prolonged [>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)
• Prior probability of undiagnosed endogenous Cushing syndrome based on either of:
• irounding of the face (especially compared with prior photos)
• Positive urine screen for recreational drugs (except tetrahydrocannabinol (THC))
• New-onset diabetes (onset <1 year in the past)
• 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 <160/100 mmHg for 1 month on a new stable medication regimen)
• Known hypersensitivity to clofutriben or to any of the product
• Unwillingness to maintain with current glucose-lowering regimen during the trial
• Unwillingness to adjust, add, replace, or discontinue current or other glucose-lowering medications during the trial as directed by the investigator
• 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
• 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:
• Glomerular filtration rate (GFR) (determined using Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) <45 mL/min/1.73 m²
• Liver enzymes >3 × upper limit of normal (ULN) (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or bilirubin >1.5 × ULN.(excepting benign conditions such as Gilbert's)
• Unwillingness to comply with CGM or other trial procedures
• Investigator considers the patient will otherwise be unwilling or unable to complete the trial
• Night-shift worker or otherwise habitually awake from 23:00 to 07:00 h
• supraclavicular/dorsocervical fat accumulation
• skin changes (violaceous striae, skin thinning, or excessive bruising)
• proximal muscle weakness on exam; or
• Poorly controlled hyperthyroidism/hypothyroidism (confirmed by TSH or Free thyroxine [fT4])