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).
CAPTAIN-T2D is a two-part, multicenter, randomized, double-blind, parallel group, placebo- controlled trial of the 11-hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitor clofutriben. The primary objectives of this trial are to characterize the relationship of clofutriben dose to improved glycemic control, and to identify one or more doses suitable for Phase 3 evaluation, in patients with T2D and elevated cortisol.
The trial consists of two parts.
Part 1 (Screening) will last between approximately 5 to 9 weeks for most participants. The screening period duration allows for (sequentially) initial eligibility screen, dexamethasone suppression test, and further eligibility assessments.
During Part 2 (Treatment), participants will be randomized to placebo or one of four clofutriben doses. Part 2 will last 24 weeks with a follow-up phone call 4 weeks after the last dose of trial medication.
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 \<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 other glucose-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 complete the trial.
* Night-shift worker or otherwise habitually awake from 23:00 to 07:00 h.
* 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).
* 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 \<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 Disease Epidemiology 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) or aspartate aminotransferase (AST) or bilirubin \>1.5 × ULN.(excepting benign conditions such as Gilbert's)
* Known hypersensitivity to clofutriben or to any of the product
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Outcomes
Primary Outcomes
Percentage of patients with both morning serum cortisol >1.8 mg/dL and morning plasma dexamethasone >=140 ng/dL (single composite endpoint) after a single dexamethasone 1 mg dose taken the prior night.
To assess prevalence in the trial population of morning cortisol non-suppression by a single dexamethasone 1 mg dose.
Time frame: 8-10 hours after the dexamethasone 1 mg dose.
Glycated hemoglobin A1c (%) change from baseline to Week 24 by treatment.
To assess glycated hemoglobin A1c (%) changes, compared to placebo, in patients who receive each of 4 daily clofutriben doses for 24 weeks.
Time frame: 24 weeks.
Secondary Outcomes
Fasting plasma glucose (mmol/L) change from baseline to Week 24 by treatment.
To assess glucose (mmol/L) changes, compared to placebo, in patients who receive each of 4 daily clofutriben doses for 24 weeks.