Overview

The purpose of this study is to evaluate the safety and tolerability of 1 mg osilodrostat therapy in patients with mild autonomous cortisol secretion (MACS), and to determine the impact on 24h urine steroid metabolome and circadian cortisol/cortisone concentrations

Eligibility

Inclusion Criteria:

• Provide written informed consent
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Age ≥ 18 years
• Diagnosed with MACS
  • At least 2 abnormal post-dexamethasone cortisol results: i. 1 mg post-dexamethasone cortisol \>1.8 mcg/dL or ii. 8 mg post-dexamethasone cortisol \>1 mcg/dL
  • Historical dexamethasone suppression test results can be used if performed within 24 months prior to enrollment.
• Adrenal imaging phenotype consistent with benign disease (adrenal adenoma/s, macronodular or micronodular adrenal hyperplasia)
• At least one of the following comorbidities:
  • Obesity (BMI\>30 kg/m2)
  • Dysglycemia
  • Dyslipidemia
  • Hypertension
  • Osteopenia
  • Osteoporosis
  • Fragility fractures
• Ability to take oral medication and be willing to adhere to the study intervention regimen
• For persons of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of ≤ 5% per year during the treatment period and for 1 month after the last dose of study treatment.

Exclusion Criteria:

• Planned alternative therapy for MACS during the study period
• Current use of oral exogenous glucocorticoid therapy
• Current use of opioid therapy \>20 MME/day
• Planned use of oral exogenous glucocorticoid therapy
• Planned use of opioid therapy \>20 MME/day
• Use of injectable glucocorticoid within the last 6 weeks or anticipated glucocorticoid use during the study period.
• Hypokalemia of hypomagnesemia at baseline visit
• Prolonged QTc on baseline ECG
• Concomitant therapy with medications likely to lead to drug-drug interactions (based on PI review).
• Investigator's judgement based on history/physical examination that a comorbidity or concomitant medication may impact the hypothalamic-pituitary-adrenal axis or steroid metabolome
• Uncontrolled intercurrent illness including, but not limited to:
  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness/social situations that would limit compliance with study requirements
• Pregnancy or lactation
• Known allergic reactions to osilodrostat
• Suspected false positive post-dexamethasone cortisol results due to increased metabolism, poor absorption, or noncompliance with dexamethasone.
• Treatment with another investigational drug or other intervention within lower than specific therapy washout period