Metyrapone Versus Osilodrostat in Patients With Metabolic Autonomous Cortisol Secretion (MACS) (MOMACS)

This study will compare the efficacy and safety of the two 11β-hydroxylase inhibitors-metyrapone and osilodrostat-in patients with MACS.

Primary outcome To compare the efficacy (biochemical and clinical) of the two 11β-hydroxylase inhibitors (CYP11B1), metyrapone and osilodrostat, in patients with MACS not treated surgically (mainly bilateral adenomas or adrenal hyperplasias), as well as their side effects at time 0-, 3- and 6-months post-treatment.

Secondary outcome To evaluate alterations in clinical parameters (Blood Pressure, Body Mass Index-BMI), metabolic parameters (fasting blood glucose, insulin, Hb1Ac, HOMA, OGTT and lipids levels) at time 0-, 3- and 6-month after the initiation of the treatment and their effect on Bone Mineral Density (BMD) 1 year post-diagnosis

Study Overview

• Status: Recruiting
• Conditions: Mild Autonomous Cortisol Secretion (MACS)
• Intervention / Treatment: Drug: Metyrapone 250 mg Oral Tablets; Drug: Osilodrostat 1 MG; Procedure: adrenalectomy; Other: Watch and wait

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Anna Angelousi, MD, PhD, Msc; Phone Number: 0030 00306978167876; Email: a.angelousi@gmail.com

Study Locations

• Greece
  • Athens, Greece
    • Recruiting
    • Laikon General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults > 18 years old with MACS and unilateral or bilateral adrenal adenomas or hyperplasia (based on imaging)
• 1 mg overnight dexamethasone suppression test (ODST): Cortisol levels at 8.00 am>1.8 μg/dl AND i) ACTH< 15 pg/ml OR ii) abnormal midnight salivary cortisol OR iii) Urinary free cortisol levels (UFC) /24h ≥ of the UNL

Exclusion Criteria:

• Abnormal liver enzymes
• eGFR < 40 ml/min/1.73 m3
• Pseudocushing syndrome
• Patients with any malignancy (active or past history), including ACC
• ACTH-dependent Cushing syndrome (Cushing disease or ectopic Cushing syndrome)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Patients with MACS; Patients with MACS (Adults > 18 years old with 1mg ODST F levels >1.8μg/dl and normal or slightly abnormal UFC OR midnight salivary cortisol levels AND no symptoms or signs of overt hypercortisolism.)	Drug: Metyrapone 250 mg Oral Tablets; metyrapone( 250 -750 mg) vs. osilodrostat (1-3 mg) vs. surgery vs watch and wait strategy in the management of patients with MACS; Other Names: surgery; osilodrostat; Drug: Osilodrostat 1 MG; administration of 1-3 mg of osilodrostat at 19.00; Procedure: adrenalectomy; Surgery performed in patients with MACS; Other: Watch and wait; Follow-up

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of the efficacy of metyrapone and osilodrostat	Blood tests measuring baseline moring cortisol (μg/dl) levels pre and post-treatment	Baseline ( at t=0), at t=3 months and at =6 months
Comparison of the efficacy of metyrapone and osilodristat	Measurement of the baseline morning ACTH (pg/ml) pre and post-treatment	Baseline (at t= 0), at t= 3 months and t= 6 months
Comparison of the efficacy of metyrapone and osilodristat	Measurement of the baseline morning DHEAS levels (μg/dl) pre and post-treatment	Baseline ( at t=0), at t=3 months and at t=6 months
Comparison of the efficacy of metyrapone and osilodristat	Measurement of urinary free cortisol (μg/24h) pre and post-treatment	Baseline ( at t=0), at t=3 months and at =6 months
Comparison of metyrapone and osilodrostat efficacy	Measurement of salivary midnight cortisol (μg/dl) pre and post-treatment	Baseline (at t=0), at t=3 months , at t =6 months
Comparison of metyrapone and osilodrostat in terms of alterations of metabolic parameters	Alteartions of LDL levels (mg/dl) pre and post-treatment	Baseline (t=0), at t= 3months, at t=6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of metyrapone and osilodrostat in terms of alterations of metabolic parameters	Alterations of fasting blood glucose levels (mg/dl) pre and post-treatment	Baseline at t=0 , at 3 months and at 6 months
Comparison of metyrapone and osilodrostat in terms of alterations of metabolic parameters	Alteration of insuline levels (μU/ml) pre and post-treatment	Baseline (t=0), at t=3 months and at t=6 months
Comparison of metyrapone and osilodrostat in terms of alterations of metabolic parameters	Alterations of Hb1Ac levels (%) pre and post-treatment	Baseline (t=0), at t=3 months and at t=6 months
Comparison of metyrapone and osilodrostat in terms of alterations of metabolic parameters	Alterations of HOMA-IR (glucose levels mmol/l x insuline levels mIU/L/22.5) pre and post -treatment	Baseline (t=0) at t=3 months and t=6 months
Comparison of metyrapone and osilodrostat in terms of alterations of metabolic parameters	Alterations of cholesterol levels (mg/dl) pre and post-treatment	Baseline (t=0), at t=3 months and at t=6 months
Comparison of metyrapone and osilodrostat in terms of alterations of metabolic parameters	Alterations of triglycerides levels (mg/dl) pre and post-treatment	Baseline (t=0), at t=3 months and at t=6 months
Comparison of metyrapone and osilodrostat in terms of alterations of metabolic parameters	Alterations of HDL levels (mg/dl) pre and post-treatment	Baseline (t=0), at t=3 months and at t=6 months
Comparison of metyrapone and osilodrostat in terms of alterations of metabolic parameters	Alterations of glucose levels post-OGTT pre and post-treatment	Baseline at t=0, at t=3 months , at t=6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of metyrapone and osilodrostat in terms of other parameters	Alterations of systolic and diastolic blood pressure (mmHg) at morning pre and post-treatment	Baseline (t=0), at t=3 months and t=6 months
Comparison of metyrapone and osilodrostat in terms of other parameters	Alterations of BMI (weight (kg) / height(cm2)) levels pre and post-treatment	Baseline (t=0), t=3 months , t=6 months
Comparison of metyrapone and osilodrostat in terms of other parameters	Alterations of bone mineral density (BMD) in gr /cm3 pre and post-treatment	Baseline at t=0 and at t= 1 year

Collaborators and Investigators

• Sponsor: Laikο General Hospital, Athens

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2025
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): November 25, 2027

Study Registration Dates

• First Submitted: November 21, 2025
• First Submitted That Met QC Criteria: December 3, 2025
• First Posted (Actual): December 5, 2025

Study Record Updates

• Last Update Posted (Actual): December 5, 2025
• Last Update Submitted That Met QC Criteria: December 3, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: cortisol; osilodrostat; Cushing; MACS; METYRAPONE
• Additional Relevant MeSH Terms: Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Endocrine Surgical Procedures; Metyrapone; Surgical Procedures, Operative; Adrenalectomy; Osilodrostat
• Other Study ID Numbers: Laikon

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No