Isturisa Treatment in Mild Autonomous Cortisol Secretion( MACS)

Mild autonomous cortisol secretion (MACS) is diagnosed in up to 48% of patients with incidentally discovered adrenal tumors or hyperplasia. Based on the finding of adrenal masses in 5% of adults undergoing cross-sectional imaging, the overall prevalence of MACS is about 1-2%. MACS is characterized by autonomous cortisol secretion without the overt symptoms of Cushing syndrome. It is usually associated with low ACTH and DHEAS levels as an indicator of autonomous cortisol secretion. The European Society of Endocrinology-European Network for the Study of Adrenal Tumors (ESE-ENSAT) and the American Association of Clinical Endocrinology (AACE) recommend a cortisol >1.8 μg/dL after 1 mg-DST to define MACS. Several metabolic abnormalities are associated with MACS, including increased cardiovascular disease, mood alteration, hypertension, osteoporosis, hyperglycemia, obesity, weight gain, and lipid abnormalities. Additionally, increased mortality has been reported in MACS patients. Given these complications and increased mortality, there is a need for effective management and treatment options for MACS.

This research aims to evaluate the efficacy and safety of Isturisa in patients with MACS to address the current gap in treatment strategies. By assessing how effectively Isturisa improves cardiometabolic disorders and monitoring its safety profile, the research will seek to provide a clearer understanding of its role as a treatment option in MACS patients who are not a surgical candidate or do not want to pursue surgery. This evaluation is crucial for developing more effective treatment options and improving management strategies for MACS, ultimately contributing to better patient management.

• Osilodrostat (Isturisa) (Drug), also known as Osilodrostat, Isturisa, LCI699: The intervention aims to evaluate the impact of osilodrostat on cardiometabolic outcomes, bone mineral density, body composition, adrenal tumor size or hyperplasia, and biochemical markers of cortisol excess.

Primary outcomes

• Change in fasting glucose, HbA1c [Baseline, and then every 3 months up to 2 years]: glycemic control: fasting glucose, HbA1c
• Change in bone mineral density (g/cm²) [Baseline, 1 year, and 2 years]: Bone mineral density (g/cm²) measured by DEXA scan.
• Change in body weight (kg) from baseline during Isturisa treatment [Baseline and every 3 months up to 2 years]: Change in body weight will be measured at baseline and every follow-up visit (approximately every 3 months) throughout the 2-year treatment period with Isturisa.
• Change in lipid profile from baseline during Isturisa treatment [Baseline and every 3 months up to 2 years]: Serum lipid profile (LDL-C, HDL-C, total cholesterol, triglycerides) will be assessed at baseline and every follow-up visit (approximately every 3 months) during the 2-year treatment period.
• Change in body composition (kg) [baseline, 1 year and 2 years]: Body composition including lean mass and fat mass (kg) measured by DEXA scan.

Secondary outcomes

• Change in Quality of Life as assessed by Short Form -36 (SF-36) [Baseline and every 3 months up to 2 years]: Assessment of changes in quality of life using the SF-36 Health Survey. The SF-36 consists of 36 items measuring 8 health domains, with total scores ranging from 0 to 100, where higher scores indicate better quality of life.
• Change in carotid intima-media thickness (CIMT) [Baseline, 1 year, and 2 years]: Carotid intima-media thickness (milimeters) will be measured using carotid ultrasound to evaluate vascular changes associated with mild autonomous cortisol secretion. CIMT will be assessed at baseline and at follow-up imaging performed approximately every 12 months during the 2-year treatment period.
• Change in adrenal adenoma/hyperplasia size (mm) [Baseline, 1 year, and 2 years]: Adenoma maximal diameter (mm) measured on non-contrast CT at each imaging time point.
• Change in Depression Scores as assessed by the Beck Depression Inventory-II [Baseline and every 3 months up to 2 years]: Assessment of changes in depressive symptoms using the Beck Depression Inventory-II (BDI-II). The BDI-II is a 21-item validated questionnaire with total scores ranging from 0 to 63, where higher scores indicate more severe depressive symptoms.

Other outcomes

• Change in Inflammatory Biomarkers [Baseline and every 3 months up to 2 years]: Exploratory evaluation of changes in inflammatory biomarkers, specifically high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6), during treatment with Isturisa in patients with mild autonomous cortisol secretion (MACS). These markers are included in the optional research-specific procedures to assess potential inflammatory or physiologic effects of Isturisa beyond cortisol regulation.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Adults aged ≥18 years.
* Diagnosis of mild autonomous cortisol secretion (MACS) defined by:
* Serum cortisol >1.8 µg/dL after 1 mg overnight dexamethasone suppression test (DST).
* Presence of adrenal adenoma confirmed by imaging (CT or MRI).
* Ability to provide informed consent.
* Willingness to undergo study procedures including DEXA scan and laboratory assessments.

Exclusion Criteria:

* Known diagnosis of Cushing's syndrome or overt hypercortisolism.
* Current or recent (within 3 months) treatment with glucocorticoids or medications affecting cortisol production (e.g., ketoconazole, metyrapone).
* Severe hepatic impairment or renal failure.
* Pregnancy or breastfeeding.
* Known allergy or contraindication to osilodrostat (Isturisa).
* Participation in another interventional clinical trial within the last 30 days.
* Any medical or psychiatric condition that, in the investigator's judgment, may interfere with study participation or safety.

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• Amir Hamrahian, MD, Principal investigator, Johns Hopkins University