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

This is study with SPI-62 to evaluate the efficacy, safety, and pharmacological effect of SPI-62 in subjects with hypercortisolism related to a benign adrenal tumor. Each subject will receive 2mg of SPI-62 daily.

This is a multicenter, open-label, single-arm study, Phase 2 study to estimate SPI-62's effect on clinical features of hypercortisolism related to a benign adrenal tumor, including diabetes/impaired glucose tolerance, hyperlipidemia, hypertension, and osteopenia. Each subject who provides consent and meets all inclusion and exclusion criteria will participate in a screening period and an open-ended treatment period. Visits occur at screening/baseline, months 1, 3, 6, 9, and 12, and then quarter-annually.

Eligibility Criteria:
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 or proven to be non malignant.
* Diagnosis of diabetes mellitus, pre-diabetes or impaired glucose tolerance, either untreated 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 or on 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 systolic or \> 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 free cortisol \> 2.2 nM (80 ng/dL).
  * For subjects with morning serum cortisol \> 138 nM (5.0 mcg/dL) after ONDST, the Investigator 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 malignancy associated hypercortisolism including history of adrenal carcinoma.
* History of adrenalectomy or planned adrenalectomy within 4 months after randomization.
* Exogenous hypercortisolism.
* Uncontrolled, clinically significant hypo- or hyperthyroidism.
* History of idiopathic thrombocytopenia.
* Moderately impaired renal function (estimated glomerular filtration rate \< 60 mL/min/1.73m2).
* History of cancer (other than non-melanoma skin, thyroid, or early-stage prostate cancer) within 3 years.
* Any major surgery, or significant post-operative sequelae, within 1 month prior to informed consent or planned during the trial.
* Pregnant or lactating.
* Positive test for severe acute respiratory syndrome coronavirus 2 infection within 4 weeks, or hospitalization for Coronavirus disease 2019 within 6 months, prior to randomization.
* Any other current or prior medical condition expected to interfere with the conduct of the trial or the evaluation of its results.
* Participation in any clinical trial within 3 months prior to the first dose of study drug, or longer depending on half-life of the investigational therapy.