Mild Autonomous Cortisol Secretion (MACS)Phase 4NCT07247058
Isturisa Treatment in Mild Autonomous Cortisol Secretion( MACS)
A Phase 4 study testing Osilodrostat (Isturisa) in people with Mild Autonomous Cortisol Secretion (MACS), run by Johns Hopkins University at 1 site in United States.
Trial summary
To characterize the impact of Isturisa on clinical features and comorbidities associated with MACS. The investigators hypothesize that patients treated with Isturisa will exhibit significantly better metabolic indicators (such as fasting glucose, HbA1c, and lipid profile), blood pressure, weight, body composition and… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Mild Autonomous Cortisol Secretion (MACS)
- What is being tested?
- Osilodrostat (Isturisa)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteUnited States
- Study dates
- 2 Feb 2026to Mar 2029
- Phase
- Phase 4
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
None listed.
Who cannot join
- Has severe, uncontrolled hypertension (mean SBP >170 mm Hg or mean Diastolic Blood Pressure (DBP) >110 mm Hg at Screening)
- Has poorly controlled DM (HbA1c >11% at Screening).
- Has abnormal liver test results (total bilirubin >1.5×ULN or elevated alanine aminotransferase or aspartate aminotransferase >3×ULN at Baseline).
- Has severe renal insufficiency (glomerular filtration rate ≤29 mL/min at Baseline).
- Has uncontrolled, clinically significant hypothyroidism or hyperthyroidism.
- Has prolonged QT interval corrected for heart rate using Fridericia's equation (QTcF) (>450 ms for men and >470 ms for women) with a normal QRS interval (<120 ms) or QTcF interval >500 ms with wide QRS interval (≥120 ms).
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- Has persistent atrial fibrillation.
- Has uncorrected hypokalemia.
- Has used or plans to use any treatments for MACS within 12 weeks before Screening and throughout the study, including metyrapone, mifepristone, ketoconazole, fluconazole, or any investigational drug for the treatment of hypercortisolism.
- Has adrenocortical carcinoma, or the adrenal images are suspicious for an underlying malignancy.
- Has autonomous co-secretion of aldosterone.
- Has plans for adrenalectomy or nodulectomy during the study.
- Pregnancy, lactating, or intends to become pregnant in the next 2 years.
- Female patients of childbearing potential who cannot use a highly effective method of contraception, including all women <50 years old, women whose surgical sterilization was performed <6 months ago.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Johns Hopkins University School of Medicine
Baltimore, Maryland, 21205
Amir Hamrahian, MD, 410-955-1578, ahamrah1@jhmi.edu
Tony Keyes, akeyes1@jhmi.edu
About this study
Official title: Isturisa in Management of Mild Autonomous Cortisol Secretion (MACS)
To characterize the impact of Isturisa on clinical features and comorbidities associated with MACS. The investigators hypothesize that patients treated with Isturisa will exhibit significantly better metabolic indicators (such as fasting glucose, HbA1c, and lipid profile), blood pressure, weight, body composition and bone mineral density than at Baseline. The investigators also assess the effect of Isturisa on quality of life and psychological symptoms in patients with MACS. The investigators hypothesize that treatment with Isturisa will lead to significant improvements in quality-of-life scores and reductions in depression scores compared to Baseline.
Read the detailed description
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.
- Being tested
- Osilodrostat (Isturisa)
- Keywords
- MACS, Mild Autonomous Cortisol Secretion, Adrenal Adenoma, Osilodrostat, Isturisa, Body Composition, Metabolic Outcomes, Subclinical Cushing Syndrome, Adrenal hyperplasia, Carotid intima thickness, Bone mineral density, Hypertension, Glycemic control
- Medical subject headings
- ACTH Syndrome, Ectopic, Adrenal Hyperplasia, Congenital, Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Osilodrostat (Isturisa)Drug
Also called 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.
| Study group | Role | What they receive |
|---|---|---|
| Isturisa Treatment Arm | Experimental | Participants diagnosed with Mild Autonomous Cortisol Secretion (MACS) will receive Osilodrostat (Isturisa) as an investigational treatment. The intervention aims to evaluate comorbidities associated with MACS after the initiation of osilodrostat(Isturisa). Receives: Drug: Osilodrostat (Isturisa) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in fasting glucose, HbA1c
glycemic control: fasting glucose, HbA1c
Measured: Baseline, and then every 3 months up to 2 years
Change in bone mineral density (g/cm²)
Bone mineral density (g/cm²) measured by DEXA scan.
Measured: Baseline, 1 year, and 2 years
Change in body weight (kg) from baseline during Isturisa treatment
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.
Measured: Baseline and every 3 months up to 2 years
Change in lipid profile from baseline during Isturisa treatment
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.
Measured: Baseline and every 3 months up to 2 years
Change in body composition (kg)
Body composition including lean mass and fat mass (kg) measured by DEXA scan.
Measured: baseline, 1 year and 2 years
Secondary outcomes (4)
Change in Quality of Life as assessed by Short Form -36 (SF-36)
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.
Measured: Baseline and every 3 months up to 2 years
Change in carotid intima-media thickness (CIMT)
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.
Measured: Baseline, 1 year, and 2 years
Change in adrenal adenoma/hyperplasia size (mm)
Adenoma maximal diameter (mm) measured on non-contrast CT at each imaging time point.
Measured: Baseline, 1 year, and 2 years
Change in Depression Scores as assessed by the Beck Depression Inventory-II
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.
Measured: Baseline and every 3 months up to 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Nov 2025
- Study start2 Feb 2026
- Primary completionDec 2028 (estimated)
- Study completionMar 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (14)Papers the sponsor has linked to this study.
- Other trials for Mild Autonomous Cortisol Secretion (MACS)Studies of the same condition, open and under way.
- More trials run by Johns Hopkins UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- This is a single-arm, interventional study in which all enrolled participants with MACS will receive Osilodrostat (Isturisa). The patients will be evaluated for the impact of Isturisa on clinical features and comorbidities associated with MACS.
- Masking
- None (open label)
- Enrolment
- 10 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Johns Hopkins University
- Sponsor type
- University, hospital or other
- Collaborators
- Recordati Rare Diseases Inc
- Responsible party
- Sponsor
- Investigators
- Amir Hamrahian, MD, Principal investigator, Johns Hopkins University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07247058
- Sponsor's protocol ID
- IRB00511675
- Status last verified
- Oct 2026
- First submitted
- 19 Nov 2025
- Last updated
- 23 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Feldman D. Ketoconazole and other imidazole derivatives as inhibitors of steroidogenesis. Endocr Rev. 1986 Nov;7(4):409-20. doi: 10.1210/edrv-7-4-409. No abstract available.
PubMed 3536461Martino M, Aboud N, Lucchetti B, Salvio G, Arnaldi G. Osilodrostat oral tablets for adults with Cushing's disease. Expert Rev Endocrinol Metab. 2022 Mar;17(2):99-109. doi: 10.1080/17446651.2022.2044789. Epub 2022 Feb 28.
PubMed 35220871Tibblin S, Dymling JF, Ingemansson S, Telenius-Berg M. Unilateral versus bilateral adrenalectomy in multiple endocrine neoplasia IIA. World J Surg. 1983 Mar;7(2):201-8. doi: 10.1007/BF01656143. No abstract available.
PubMed 6135282Ma L, Yin L, Hu Q. Therapeutic compounds for Cushing's syndrome: a patent review (2012-2016). Expert Opin Ther Pat. 2016 Nov;26(11):1307-1323. doi: 10.1080/13543776.2016.1217331. Epub 2016 Jul 30.
PubMed 27454103Ren X, Nan M, Zhang X. Evaluating the efficacy of surgical and conservative approaches in mild autonomous cortisol secretion: a meta-analysis. Front Endocrinol (Lausanne). 2024 Jul 17;15:1399311. doi: 10.3389/fendo.2024.1399311. eCollection 2024.
PubMed 39086899Sbardella E, Minnetti M, D'Aluisio D, Rizza L, Di Giorgio MR, Vinci F, Pofi R, Giannetta E, Venneri MA, Vestri A, Morelli S, Lenzi A, Isidori AM. Cardiovascular features of possible autonomous cortisol secretion in patients with adrenal incidentalomas. Eur J Endocrinol. 2018 May;178(5):501-511. doi: 10.1530/EJE-17-0986. Epub 2018 Mar 6.
PubMed 29510982Patrova J, Kjellman M, Wahrenberg H, Falhammar H. Increased mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: a 13-year retrospective study from one center. Endocrine. 2017 Nov;58(2):267-275. doi: 10.1007/s12020-017-1400-8. Epub 2017 Sep 8.
PubMed 28887710Pelsma ICM, Fassnacht M, Tsagarakis S, Terzolo M, Tabarin A, Sahdev A, Newell-Price J, Marina L, Lorenz K, Bancos I, Arlt W, Dekkers OM. Comorbidities in mild autonomous cortisol secretion and the effect of treatment: systematic review and meta-analysis. Eur J Endocrinol. 2023 Oct 17;189(4):S88-S101. doi: 10.1093/ejendo/lvad134.
PubMed 37801655Czapla-Iskrzycka A, Swiatkowska-Stodulska R, Sworczak K. Comorbidities in Mild Autonomous Cortisol Secretion - A Clinical Review of Literature. Exp Clin Endocrinol Diabetes. 2022 Sep;130(9):567-576. doi: 10.1055/a-1827-4113. Epub 2022 Jul 11.
PubMed 35817047Vaidya A, Hamrahian A, Bancos I, Fleseriu M, Ghayee HK. THE EVALUATION OF INCIDENTALLY DISCOVERED ADRENAL MASSES. Endocr Pract. 2019 Feb;25(2):178-192. doi: 10.4158/DSCR-2018-0565.
PubMed 30817193Fassnacht M, Tsagarakis S, Terzolo M, Tabarin A, Sahdev A, Newell-Price J, Pelsma I, Marina L, Lorenz K, Bancos I, Arlt W, Dekkers OM. European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2023 Jul 20;189(1):G1-G42. doi: 10.1093/ejendo/lvad066.
PubMed 37318239Trandafir AI, Ghemigian A, Ciobica ML, Nistor C, Gurzun MM, Nistor TVI, Petrova E, Carsote M. Diabetes Mellitus in Non-Functioning Adrenal Incidentalomas: Analysis of the Mild Autonomous Cortisol Secretion (MACS) Impact on Glucose Profile. Biomedicines. 2024 Jul 18;12(7):1606. doi: 10.3390/biomedicines12071606.
PubMed 39062179Zavatta G, Vicennati V, Altieri P, Tucci L, Colombin G, Coscia K, Mosconi C, Balacchi C, Fanelli F, Malagrino M, Magagnoli M, Golfieri R, Pagotto U, Di Dalmazi G. Mild autonomous cortisol secretion in adrenal incidentalomas and risk of fragility fractures: a large cross-sectional study. Eur J Endocrinol. 2023 Apr 4;188(4):343-352. doi: 10.1093/ejendo/lvad038.
PubMed 36952249Delivanis DA, Athimulam S, Bancos I. Modern Management of Mild Autonomous Cortisol Secretion. Clin Pharmacol Ther. 2019 Dec;106(6):1209-1221. doi: 10.1002/cpt.1551. Epub 2019 Aug 6.
PubMed 31206616