Trial Against INtractable Type 2 Diabetes (CAPTAIN-T2D)

Inclusion Criteria:

• From Screening 1

• Age at least 18 years.

• HbA1c ≥7.5% documented within 3 months prior to Screening 1. (The historicalHbA1c value must have been obtained after at least 2 months on the current [asof Screening 1] regimen).

• Treatment with stable and adequate doses of ≥2 injectable or oral ADMs. (An ADMwill be deemed stable if the dose has been the same for at least 3 months priorto Screening 1 and without change between Screening 1 and Day 1) (An ADM dosewill be deemed adequate if it is at or above the maximal labelled dose, or asub-maximal, but not starting, dose if limited by tolerability (confer with MMif less than half-maximal dose).

• Adequate total daily insulin is defined as at least 0.3 units/kg/day. Insulindose will be deemed stable with adjustments of up to 20% total daily doseduring 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 orshortage) 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 atleast 1 other ADM; and

• adequately dosed incretin agonist (a single or combination agent counts asone 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 ofhypercortisolism 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 toDay 1.

Exclusion Criteria:

• New-onset diabetes (onset <1 year in the past).

• Unwillingness to maintain with current glucose-lowering regimen during the trial.

• Unwillingness to adjust, add, replace, or discontinue current or otherglucose-lowering medications during the trial as directed by the investigator.

• Unwillingness to comply with CGM or other trial procedures.

• Investigator considers the patient will otherwise be unwilling or unable to completethe trial.

• Night-shift worker or otherwise habitually awake from 23:00 to 07:00 h.

• Evidence for significant hypoglycemia while on their current diabetic treatmentregimen(This includes episodes of symptomatic Level 3 hypoglycemia requiringexternal assistance for recovery, or CGM-documented prolonged [>15 min] or repeatedepisodes of either Level 2 hypoglycemia leading to >1%, or Level 1 hypoglycemialeading to >4%, in "time below range" within 3 months prior to Screening 1 orbetween Screening 1 and Day 1).

• Any of the following in medical history:

• Type 1 diabetes mellitus (T1D), latent autoimmune diabetes in adults (LADA), orfamilial forms of maturity-onset diabetes of the young (MODY);

• A hemoglobinopathy or other condition which may interfere with measurement ofHbA1c (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 controlledwith Continuous Positive Airway Pressure (CPAP) use for at least 3 months priorto Screening 1 are not excluded. Patients with a STOP-BANG score 5-8 should bereferred for a sleep study outside the trial and may rescreen if found not tohave moderate-to-severe sleep apnea);

• Current alcohol consumption >14 units/week or >4 units in a single day formales, or >7 units/week or >3 units in a single day for females. (Patients witha CAGE score 2-4 should be evaluated further outside the trial and may berescreened if found not to have an alcohol [or other substance] use disorder);

• Untreated or inadequately controlled major depressive disorder, generalizedanxiety disorder, bipolar disorder, post-traumatic stress disorder, orschizophrenia.(Patients whose condition has been well controlled with stablemedical therapy, or has been asymptomatic, for at least 3 months prior toScreening 1 are not excluded); or

• Any other medical condition (including malignancy) that is likely to interferewith 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 thedrug's half-life, whichever is longer, prior to Screening 1 or betweenScreening 1 and Day 1;

• Woman of childbearing potential (WOCBP) not willing to adhere to highlyeffective contraception or strict abstinence for the duration of the trial andfor 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/dLtogether with plasma dexamethasone >140 ng/mL; or

• a morning serum cortisol value after dexamethasone suppression >1.8 mcg/dL, togetherwith plasma dexamethasone >140 ng/mL and any one of the following that is notattributable 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 syndromeor ACS within the next 8 months. (For clarity, patients with EnCS or ACS, not havingsuch treatment plans, and medically able to forego treatment for 8 months may enrollif otherwise eligible).

• Severe, poorly controlled hypertension (mean systolic BP >160 mmHg or mean diastolicBP >100 mmHg) at Screening 2 or between Screening 2 and Day 1, including by at-homemonitoring. (Such patients will be eligible to rescreen for Part 2 when they restoreBP <160/100 mmHg for 1 month on a new stable medication regimen).

• Positive urine screen for recreational drugs (except tetrahydrocannabinol (THC)).

• Glomerular filtration rate (GFR) (determined using Chronic Kidney DiseaseEpidemiology Collaboration [CKD-EPI]) <45 mL/min/1.73 m².

• Poorly controlled hyperthyroidism/hypothyroidism (confirmed by TSH or Free thyroxine [fT4]).

• Liver enzymes >3 × upper limit of normal (ULN) (alanine aminotransferase (ALT) oraspartate aminotransferase (AST) or bilirubin >1.5 × ULN.(excepting benignconditions such as Gilbert's)

• Known hypersensitivity to clofutriben or to any of the product