CUSHMAH - Benefit of steroidogenesis inhibitors in Mild Cushing syndrome (Mild Autonomous Cortisol Secretion): a randomized trial in patients with Primary Bilateral Macronodular Adrenocortical Hyperplasia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18], Diseases [C] - Hormonal diseases [C19]

Decision date (initial)

2026-03-05

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

ESTEVE Pharmaceuticals · Ministry of Health - PHRC

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

Demonstrate that cortisol secretion inhibition by medical treatment (metyrapone) in PBMAH patients with MACS lead to improvement of hypertension and diabetes.

Secondary objectives 7

1. Determine the level of steroid inhibition, the ACTH and the steroid profile response to steroidogenesis inhibitor (metyrapone) in PBMAH patients with MACS
2. Investigate the effect of cortisol secretion inhibition by medical treatment (metyrapone) in PBMAH patients with MACS on Body Mass Index, insulin sensitivity and lipid profile
3. Quantitatively assess the effects of metyrapone versus placebo over time on Blood Pressure as measured by 24h ABPM
4. Quantitatively assess the effects of metyrapone versus placebo over time on HbA1c
5. Analyze the impact of metyrapone on the quality of life and depression
6. Investigate genetic factors associated with hormonal and clinical response to metyrapone in PBMAH
7. Safety in term of occurrence of adrenal insufficiency

Conditions and MedDRA coding

Primary Bilateral Macronodular Adrenal Hyperplasia causing moderate Cushing Syndrome (Mild autonomous Cortisol secretion)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Age ≥ 18 years old
2. Patient with PBMAH as determined by adrenal imaging (CT-scan and/or MRI) showing multiples bilateral supracentrimetric adrenal nodules
3. Mild autonomous cortisol secretion: plasma cortisol after 1 mg overnight dexamethasone test > 50 nmol/L, 24 h Urinary free cortisol < 1,5 upper limit of Normal
4. Adrenal origin of cortisol excess: morning plasma ACTH < 10 pg/ml or between 10 and 20 pg/ml non responsive to CRH stimulation (stimulation < 50 %)
5. Hypertension (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg) or treated hypertension and/or diabetes that can be treated with antidiabetic treatments (WHO criteria)
6. For women of childbearing potential (WOCBP), negative bHCG and highly effective contraception
7. For male, an effective method of contraception
8. Signed a written informed consent
9. Affiliated to social security regime or an equivalent system
10. French speaking

Exclusion criteria 15

1. Patients with a Cushing syndrome from another causes than PBMAH
2. Patients with proven primary adrenal insufficiency
3. Under glucocorticoid (systemic or high dose local) treatment
4. Contraindication to steroidogenesis inhibitor
5. Hypersensitivity to the active substance or to one of its excipients
6. Uncontrolled diabetes (HBA1c > 9 %)
7. Loop diuretics and thiazide or thiazide-like diuretic that can cause hypokaliemia
8. Patients at high risk of cardiac rhythm disorders with QT/QTc interval > 470ms (for women) and > 450ms (for men)
9. Drugs with a known risk of QT prolongation as listed in https://crediblemeds.org
10. Pregnancy or breastfeeding women
11. Steroidogenesis inhibitor treatment less than 6 weeks before inclusion
12. Pathology that is life-threatening in the short term (1 year)
13. Patients with major psychiatric disorders that may interfere with the smooth running of the study
14. Patients on AME (state medical aid)
15. Participation to another clinical trial on medicinal products for human use

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. At 6 months of treatment number of patients achieving: 1) improvement of blood pressure control and/or 2) improvement of diabetes

Secondary endpoints 7

1. Change of urinary cortisol, salivary cortisol during the circadian rhythm, steroid profile (mass spectrometry analysis) and morning ACTH plasma level at M0, M3 and M6
2. Evolution of Body Mass Index, insulin sensitivity as determined by HOMA, glycemia as determined by glucose continuous monitoring, total cholesterol, HDL, LDL, triglyceride at M0, M3 and M6
3. Mean change from baseline to M6 in day-time and night-time Systolic and Diastolic Blood Pressure irrespective of antihypertensive treatment adaptations
4. Mean change from baseline to M6 in HbA1c irrespective of antidiabetic treatment adaptations
5. Change in the score of the 3 following quality of life and depression questionnaires at M0, M3 and M6: Medical Outcomes Study 36-item short-form health survey (SF-36), the Beck depression inventory (BECK BDI-II) and the QolCushing
6. Comparaison of the hormonal and clinical response according to the ARMC5, PDE11A4 and NR3C1 genotypes.
7. Collecting data on adverse events

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Jérôme BERTHERAT (Coordinating investigator)

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Touria EL AAMRI (project manager)

Locations

1 EU/EEA country · 13 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 29 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications