SPI-62 As a Treatment for Hypercortisolism Related to a Benign Adrenal Tumor

Inclusion Criteria:

Diagnosis and main criteria for inclusion and exclusion:

The following are the main inclusion criteria:

• Adults able to provide informed consent.

• Documented characteristically benign adrenal nodule, with diameter ≤ 4 cm,homogenous texture, and non-contrast computerized tomography ≤ 20 HU attenuation orproven to be non malignant.

• Diagnosis of diabetes mellitus, pre-diabetes or impaired glucose tolerance, eitheruntreated or on stable standard of care treatment, based on at least one of:

• HbA1c ≥ 5.7% but not > 9.5%

• 2-hour glucose level ≥ 7.8 mmol (140 mg/dL) on a 75 g OGTT

• At least one additional documented cortisol-related morbidities, either untreated oron stable standard of care treatment:

• hypercholesterolemia with total cholesterol > 3.9 mM (150 mg/dL);

• hypertriglyceridemia with triglycerides > 2.3 mM (200 mg/dL);

• osteopenia with bone densitometry Z-score < -2.0 or T-score < -1.0;

• history or evidence of minimally traumatic or osteoporotic fracture; or

• hypertension with resting supine blood pressure > 130 but < 180 mmHg systolicor > 85 but < 120 mmHg diastolic.

• Poorly suppressible hypercortisolemia:

• Morning serum cortisol > 50 nM (1.8 mcg/dL) after a 1 mg ONDST.

• Subjects with dexamethasone < 3.3 nmol/L (130 ng/dL) will undergo a high-dose (8 mg) ONDST.

• Subjects who take estrogen-containing medicines will be evaluated based on freecortisol > 2.2 nM (80 ng/dL).

• For subjects with morning serum cortisol > 138 nM (5.0 mcg/dL) after ONDST, theInvestigator will assess for adrenal Cushing's syndrome.

Exclusion Criteria:

• Diagnosis of ACTH-dependent Cushing's syndrome, pheochromocytoma, aldosteronoma,adrenocortical carcinoma, or congenital adrenal hyperplasia, or other malignancyassociated hypercortisolism including history of adrenal carcinoma.

• History of adrenalectomy or planned adrenalectomy within 4 months afterrandomization.

• Exogenous hypercortisolism.

• Uncontrolled, clinically significant hypo- or hyperthyroidism.

• History of idiopathic thrombocytopenia.

• Moderately impaired renal function (estimated glomerular filtration rate < 60mL/min/1.73m2).

• History of cancer (other than non-melanoma skin, thyroid, or early-stage prostatecancer) within 3 years.

• Any major surgery, or significant post-operative sequelae, within 1 month prior toinformed consent or planned during the trial.

• Pregnant or lactating.

• Positive test for severe acute respiratory syndrome coronavirus 2 infection within 4weeks, or hospitalization for Coronavirus disease 2019 within 6 months, prior torandomization.

• Any other current or prior medical condition expected to interfere with the conductof the trial or the evaluation of its results.

• Participation in any clinical trial within 3 months prior to the first dose of studydrug, or longer depending on half-life of the investigational therapy.