Cushing Disease Due to Increased ACTH Secretion
Conditions
Keywords
Cushing's disease, Osilodrostat, cabergoline, adrenal insufficiency, hypertension, hypokalemia, Hyperandrogenism, serum cortisol, serum dehydroepiandrosterone acetate, adrenocorticotrophic hormone, QT interval
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?
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
DRUGosilodrostat
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).
DRUGosilodrostat 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.
Sponsors
University of Basrah
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in serum cortisol | At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks. | serum cortisol (8-9 am and 6-7 pm). |
| Number of patients achieved serum cortisol (7-12 Mg/dL) | 4 weeks, 8 weeks, 12 weeks, 24, weeks, 36 weeks, and 48 weeks. | measurement of 8-9 am serum cortisol. |
| Changes in Cushing 's Quality-of-Life questionnaire 12-items (CushingQoL) score for the patients quality of life. | At 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in the patients' Body weight (kg) | At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks. | measurement of the patients' body weight using scale in the early morning and fasting, bare feet, light clothes, using electronic scale. |
| 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. | Measurement of the patients' blood pressure (SBP/DBP mmHg) using standard electronic arm cuff blood pressure machine. |
| Changes in HbA1c (%) | At 12 weeks, 24 weeks, 36 weeks, and 48 weeks. | measurement of the patients HbA1c % using BioRad D10 |
| 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. | 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. |
| Changes in plasma ACTH | At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks. | measurement of early morning plasma ACTH (pg/ml) |
| Changes in serum dehydroepiandrosterone acetate (Mg/dl) | At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks. | measurement of serum dehydroepiandrosterone acetate (Mg/dl) |
| Changes in the corrected QT interval on electrocardiograph (ECG). | At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks. | Performance of ECG for assessment and record of the c QT interval. |
| Changes in serum potassium | At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks. | measurement of serum potassium |
| Development of symptoms of hypoadrenalism | At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks. | Development of symptoms of hypoadrenalism in the form of (anorexia, nausea, vomiting, fatigue, abdominal pain, dizziness, and hypotension) |
| Number of patients will have morning serum cortisol less than (5 Mg/dl) | At 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks. | measurement of serum cortisol in the morning and fasting state. |
Countries
Iraq
Contacts
PRINCIPAL_INVESTIGATORHaider A Alidrisi
Univeristy of basrah, Faiha Specialized Diabetes, Endocrine, and Metabolism Center
PRINCIPAL_INVESTIGATORIbrahim H Hussein, MD
Univeristy of basrah, Faiha Specialized Diabetes, Endocrine, and Metabolism Center
STUDY_CHAIRAbbas A Mansour
Univeristy of basrah, Faiha Specialized Diabetes, Endocrine, and Metabolism Center
Outcome results
None listed