single-center, randomized, double-blind, placebo-controlled Phase 2 study to evaluate safety and efficacy of overnight metyrapone in patients with MACS.

This study is a double blind, placebo-controlled phase II trial of the safety and efficacy of Metyrapone, in the treatment of MACS. Subjects will be remotely screened and interested qualified subjects will be remotely consented. Subjects will be randomized 2:1 for 6 months of the main study. At 6 months, two options will be available for subjects for months 6-12: open-label arm, observational arm.

Inclusion Criteria:

1. Provide written informed consent.

2. Stated willingness to comply with all study procedures and availability for the duration of the study.

3. Age ≥ 18 years

4. Diagnosed with MACS i. at least 2 abnormal post-dexamethasone cortisol results1 mg post-dexamethasone cortisol >1.8 mcg/dL or ii. 8 mg post-dexamethasone cortisol >1 mcg/dL b. Historical dexamethasone suppression test results can be used if performed within 24 months prior to enrollment.

5. Adrenal imaging phenotype consistent with benign disease (adrenal adenoma/s, macronodular or micronodular adrenal hyperplasia)

6. At least one of the following comorbidities:

   1. obesity (BMI>30 kg/m2)
   2. dysglycemia
   3. dyslipidemia
   4. hypertension
   5. osteopenia
   6. osteoporosis
   7. fragility fractures

7. Ability to take oral medication and be willing to adhere to the study intervention regimen.

8. 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.

9. Stable timing for bedtime for at least one week prior to on-site study visits.

10. History of difficulty providing blood via standard blood draw methods

Exclusion Criteria:

1. Planned alternative therapy for MACS within 12 months after joining the study.

2. Current use of oral exogenous glucocorticoid therapy

3. Current use of opioid therapy >20 MME/day

4. Planned use of oral exogenous glucocorticoid therapy

5. Planned use of opioid therapy >20 MME/day

6. Use of injectable glucocorticoid within 6 weeks prior to Day 1

7. Investigator's judgement based on history/physical examination that a comorbidity or concomitant medication may impact the hypothalamic-pituitary-adrenal axis or steroid metabolome

8. 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

9. Pregnancy or lactation

10. Known allergic reactions to metyrapone

11. Suspected false positive post-dexamethasone cortisol results due to increased metabolism, poor absorption, or noncompliance with dexamethasone

12. Treatment with another investigational drug or other intervention within lower than specific therapy washout period