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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?
In this study, adult patients with active CD (with or without previous TSS or radiotherapy) will be enrolled. Investigators will start treatment for all with Osilodrostat using up-titrating doses on bi-weekly bases. Then the patients will be randomized into two groups. For the first group, carbergoline with escalating doses will be added. For the second group, the patients will continue osilodrostat treatment with increasing doses. Through the period of the study interventions, the patients will be followed clinically, and biochemical looking for treatment related efficacy and safety.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Osilodrostat alone | Active Comparator | Osilodrostat up to 15 mg daily |
|
| Combination osilodrostat and cabergoline | Active Comparator | Osilodrostat up to 5 mg daily plus Cabergoline up to 3 mg weekly |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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). |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in the patients' Body weight (kg) | measurement of the patients' body weight using scale in the early morning and fasting, bare feet, light clothes, using electronic scale. | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Other drug related side effects | Side effects of Osilodrostat and cabergoline | At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| 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 |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Faiha Specialized Diabetes, Endocrine, and Metabolism Center | Basra | 61001 | Iraq | |||
| Al-Hassan Metabolism Endocrine and Diabetes Center |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28007845 | Background | 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. | |
| 39881009 |
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Only IPD used in the results publication.
Beginning 3 months and ending 3 years after the publication of results.
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| ID | Term |
|---|---|
| D047748 | Pituitary ACTH Hypersecretion |
| D000309 | Adrenal Insufficiency |
| D006973 | Hypertension |
| D007008 | Hypokalemia |
| D017588 | Hyperandrogenism |
| ID | Term |
|---|---|
| D006964 | Hyperpituitarism |
| D010900 | Pituitary Diseases |
| D007027 | Hypothalamic Diseases |
| D001927 | Brain Diseases |
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| ID | Term |
|---|---|
| C553306 | Osilodrostat |
| D000077465 | Cabergoline |
| ID | Term |
|---|---|
| D004873 | Ergolines |
| D004876 | Ergot Alkaloids |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
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| 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. |
|
Measurement of the patients' blood pressure (SBP/DBP mmHg) using standard electronic arm cuff blood pressure machine. |
| At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks. |
| Changes in HbA1c (%) | measurement of the patients HbA1c % using BioRad D10 | 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 | Acne will be assessed by clinical examination and reported as improved or increased. Hirsutism will be assessed using the changes in the modified Ferrimann-Gallwey (mFG) score (0 - 36), the highest the score, the more severe hirsutism. | At 12 weeks, 24 weeks, 36 weeks, and 48 weeks. |
| Changes in plasma ACTH | measurement of early morning plasma ACTH (pg/ml) | At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks. |
| Changes in serum dehydroepiandrosterone acetate (Mg/dl) | measurement of serum dehydroepiandrosterone acetate (Mg/dl) | At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks. |
| Changes in the corrected QT interval on electrocardiograph (ECG). | Performance of ECG for assessment and record of the c QT interval. | At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks. |
| Changes in serum potassium | measurement of serum potassium | At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks. |
| Development of symptoms of hypoadrenalism | Development of symptoms of hypoadrenalism in the form of (anorexia, nausea, vomiting, fatigue, abdominal pain, dizziness, and hypotension) | At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks. |
| Number of patients will have morning serum cortisol less than (5 Mg/dl) | measurement of serum cortisol in the morning and fasting state. | At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks. |
| Karbala |
| Iraq |
| Al-Waffa Specialized Center for Diabetes and Endocrinology | Mosul | Iraq |
| Najaf Specialized Diabetes and Endocrine Center | Najaf | Iraq |
| Thi-Qar Specialized Diabetes, Endocrine and Metabolism Center | Nasiriyah | Iraq |
| 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. |
| 35325149 | 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. |
| 25647330 | 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. |
| D002493 |
| Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D004700 | Endocrine System Diseases |
| D000307 | Adrenal Gland Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D014883 | Water-Electrolyte Imbalance |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D058489 | 46, XX Disorders of Sex Development |
| D012734 | Disorders of Sex Development |
| D014564 | Urogenital Abnormalities |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D047808 | Adrenogenital Syndrome |
| D052801 | Male Urogenital Diseases |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D006058 | Gonadal Disorders |
| D006576 |
| Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |