Combination Osilodrostat and Cabergoline in Cushing's Disease

NCT07603466 | Enrolling By Invitation Phase 4 DMC

• 1 other identifier: 05/13/26
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 5

Brief Summary

Cushing disease remains a challenging endocrine disorder in which persistent or recurrent hypercortisolism often requires medical therapy after surgery or when surgery is not feasible. Combination medical therapy has emerged as a rational strategy to improve biochemical control through complementary mechanisms while potentially reducing treatment escape and dose-related toxicity. Cabergoline exerts pituitary D2-receptor-mediated inhibition of ACTH secretion and may provide partial cortisol control in selected patients, although treatment escape and variable durability remain important limitations. Osilodrostat is a potent 11β-hydroxylase inhibitor that produces rapid and often substantial reductions in cortisol secretion, with clinical improvement in metabolic and cardiovascular features of hypercortisolism. The osilodrostat-cabergoline combination is mechanistically attractive because it pairs central ACTH suppression with peripheral blockade of cortisol synthesis, but published evidence remains limited to small real-world experiences and does not yet define optimal sequencing, dosing, or long-term benefit. Safety considerations include adrenal insufficiency from overtreatment, osilodrostat-associated hypertension from mineralocorticoid precursor accumulation, and hyperandrogenism due to steroid precursor shunting. Combination medical therapy in Cushing disease is a promising individualized approach, and the osilodrostat-cabergoline pairing is biologically plausible and potentially effective, but current literature is insufficient to support firm recommendations regarding efficacy, safety, or patient selection. The study aims to evaluate whether a combination can result in rapid, more control of Cushing's disease (clinically and biochemically)? Can cabergoline reduces Osilodrostat dose requirement, reduces Osilodrostat related mineralocorticoid and hyperandrogenism side effects?

Conditions

Cushing Disease Due to Increased ACTH Secretion

Keywords

Cushing's disease; Osilodrostat; cabergoline; adrenal insufficiency; hypertension; hypokalemia; Hyperandrogenism; serum cortisol; serum dehydroepiandrosterone acetate; adrenocorticotrophic hormone; QT interval

Outcome Measures

Primary Outcomes (3)

• Changes in serum cortisol

  serum cortisol (8-9 am and 6-7 pm).

  At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks.

• Number of patients achieved serum cortisol (7-12 Mg/dL)

  measurement of 8-9 am serum cortisol.

  4 weeks, 8 weeks, 12 weeks, 24, weeks, 36 weeks, and 48 weeks.

• Changes in Cushing 's Quality-of-Life questionnaire 12-items (CushingQoL) score for the patients quality of life.

  Changes in CushingQoL (12 items) questionnaire. The lowest score is 12 and highest score is 60. The highest the score, the better life quality and clinical improvement in Cushing syndrome.

  At 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks.

Secondary Outcomes (10)

• Changes in the patients' Body weight (kg)

  At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks.

• Changes in the patients' Blood pressure (increase or decrease) and increase or decrease requirements for blood pressure lowering medications.

  At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks.

• Changes in HbA1c (%)

  At 12 weeks, 24 weeks, 36 weeks, and 48 weeks.

• Assessment of clinical hyperandrogenic features (acne and hirsutism), whether increase or decrease for female patients

  At 12 weeks, 24 weeks, 36 weeks, and 48 weeks.

• Changes in plasma ACTH

  At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks.

Other Outcomes (1)

• Other drug related side effects

  At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks.

Study Arms (2)

Osilodrostat alone

ACTIVE COMPARATOR

Osilodrostat up to 15 mg daily

Drug: osilodrostat

Combination osilodrostat and cabergoline

ACTIVE COMPARATOR

Osilodrostat up to 5 mg daily plus Cabergoline up to 3 mg weekly

Drug: osilodrostat and cabergoline

Interventions

osilodrostat DRUG

1 mg (pill) twice daily for two weeks, titrated to 2.5 mg (5 mg pill divided) twice daily for two weeks, then 7.5 (half 5 mg pill and 5 mg pill) for four weeks, then 10 mg (5 mg pill twice daily) for four weeks, then 15 mg (5 mg pill thrice daily).

Osilodrostat alone

osilodrostat and cabergoline DRUG

1 mg (pill) twice daily for two weeks, titrated to 2.5 mg (5 mg pill divided) twice daily for two weeks, then Add: Cabergoline 0.5 mg twice weekly for four weeks, titrated to 1 mg twice weekly for four weeks, then 1 mg thrice weekly.

Combination osilodrostat and cabergoline

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Cushing's disease: Not treated or received treatment (TSS and/or radio surgery). And
• Active disease confirmed with repeated two biochemical tests (1-mg overnight dexamethasone suppression test and late night salivary cortisol), And
• Inappropriate ACTH elevation, And
• Positive ACTH response to desmopressin stimulation test, And
• MRI finding of pituitary adenoma.

You may not qualify if:

• Severe hepatic impairment (Child-Pugh C).
• Pregnancy.

Sponsors & Collaborators

• University of Basrah: lead

Study Sites (5)

Faiha Specialized Diabetes, Endocrine, and Metabolism Center

Basra, 61001, Iraq

Location

Al-Hassan Metabolism Endocrine and Diabetes Center

Karbala, Iraq

Location

Al-Waffa Specialized Center for Diabetes and Endocrinology

Mosul, Iraq

Location

Najaf Specialized Diabetes and Endocrine Center

Najaf, Iraq

Location

Thi-Qar Specialized Diabetes, Endocrine and Metabolism Center

Nasiriyah, Iraq

Location

Related Publications (4)

• Ferriere A, Cortet C, Chanson P, Delemer B, Caron P, Chabre O, Reznik Y, Bertherat J, Rohmer V, Briet C, Raingeard I, Castinetti F, Beckers A, Vroonen L, Maiter D, Cephise-Velayoudom FL, Nunes ML, Haissaguerre M, Tabarin A. Cabergoline for Cushing's disease: a large retrospective multicenter study. Eur J Endocrinol. 2017 Mar;176(3):305-314. doi: 10.1530/EJE-16-0662. Epub 2016 Dec 22.

  PMID: 28007845 BACKGROUND

• Giustina A, Uygur MM, Frara S, Barkan A, Biermasz NR, Chanson P, Freda P, Gadelha M, Haberbosch L, Kaiser UB, Lamberts S, Laws E, Nachtigall LB, Popovic V, Schilbach K, Lely AJV, Wass JAH, Melmed S, Casanueva FF. Medical management pathways for Cushing's disease in pituitary tumors centers of excellence (PTCOEs). Pituitary. 2025 Jan 29;28(1):23. doi: 10.1007/s11102-024-01485-x.

  PMID: 39881009 BACKGROUND

• Gadelha M, Bex M, Feelders RA, Heaney AP, Auchus RJ, Gilis-Januszewska A, Witek P, Belaya Z, Yu Y, Liao Z, Ku CHC, Carvalho D, Roughton M, Wojna J, Pedroncelli AM, Snyder PJ. Randomized Trial of Osilodrostat for the Treatment of Cushing Disease. J Clin Endocrinol Metab. 2022 Jun 16;107(7):e2882-e2895. doi: 10.1210/clinem/dgac178.

  PMID: 35325149 BACKGROUND

• Vilar L, Naves LA, Machado MC, Bronstein MD. Medical combination therapies in Cushing's disease. Pituitary. 2015 Apr;18(2):253-62. doi: 10.1007/s11102-015-0641-x.

  PMID: 25647330 BACKGROUND

MeSH Terms

Conditions

Pituitary ACTH Hypersecretion; Adrenal Insufficiency; Hypertension; Hypokalemia; Hyperandrogenism

Interventions

Osilodrostat; Cabergoline

Condition Hierarchy (Ancestors)

Hyperpituitarism; Pituitary Diseases; Hypothalamic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Adrenal Gland Diseases; Vascular Diseases; Cardiovascular Diseases; Water-Electrolyte Imbalance; Metabolic Diseases; Nutritional and Metabolic Diseases; 46, XX Disorders of Sex Development; Disorders of Sex Development; Urogenital Abnormalities; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Adrenogenital Syndrome; Male Urogenital Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Gonadal Disorders

Intervention Hierarchy (Ancestors)

Ergolines; Ergot Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring

Study Officials

• Haider A Alidrisi

  Univeristy of basrah, Faiha Specialized Diabetes, Endocrine, and Metabolism Center

  PRINCIPAL INVESTIGATOR

• Ibrahim H Hussein, MD

  Univeristy of basrah, Faiha Specialized Diabetes, Endocrine, and Metabolism Center

  PRINCIPAL INVESTIGATOR

• Abbas A Mansour

  Univeristy of basrah, Faiha Specialized Diabetes, Endocrine, and Metabolism Center

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: May 11, 2026
• First Posted: May 22, 2026
• Study Start: May 11, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): August 1, 2028
• Last Updated: May 22, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 3 months and ending 3 years after the publication of results.

Locations

IR (5)