Combination Osilodrostat and Cabergoline in Cushing's Disease

Official title

Combination Osilodrostat and Cabergoline Versus Osilodrostat Alone in Cushing's Disease in Iraq: Assessment of Efficacy and Safety

Overview

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?

Detailed description

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.

Interventions

• Drug osilodrostat
  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).
• Drug osilodrostat and cabergoline
  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.

Primary outcome measures

• Changes in serum cortisol [Time frame: 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) [Time frame: 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. [Time frame: At 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks.]

Secondary outcome measures (10)

• Changes in the patients' Body weight (kg) [Time frame: 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. [Time frame: At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks.]
• Changes in HbA1c (%) [Time frame: 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 [Time frame: At 12 weeks, 24 weeks, 36 weeks, and 48 weeks.]
• Changes in plasma ACTH [Time frame: At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks.]
• Changes in serum dehydroepiandrosterone acetate (Mg/dl) [Time frame: 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). [Time frame: At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks.]
• Changes in serum potassium [Time frame: At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks.]
• Development of symptoms of hypoadrenalism [Time frame: 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) [Time frame: At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks.]

Eligibility criteria

Inclusion criteria

• 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.

Exclusion criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Iraq · 5 centers

• Faiha Specialized Diabetes, Endocrine, and Metabolism Center — Basra
• Al-Hassan Metabolism Endocrine and Diabetes Center — Karbala
• Al-Waffa Specialized Center for Diabetes and Endocrinology — Mosul
• Najaf Specialized Diabetes and Endocrine Center — Najaf
• Thi-Qar Specialized Diabetes, Endocrine and Metabolism Center — Nasiriyah

Publications

• 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
• 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
• 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
• 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

Identifiers

NCT: NCT07603466 · 05/13/26

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗