Cushing Syndrome, Hypercortisolemia, Hypertension
Conditions
Keywords
osilodrostat, hypertension, hypercolesterolaemia, cushing's syndrome
Brief summary
Osilodrostat has proven to be a safe and efficacious treatment for patients with CS. Demonstrating normalisation of hypercortisolaemia and in patients with hypertension and/or dysglycaemia clinically relevant and statistically significant reductions in blood pressure and glycaemia. This study aims at providing additional evidence on the safety, efficacy and appropriate dosing of osilodrostat in patients with CS, who have hypertension.
Interventions
DRUGOsilodrostat
Osilodrostat tablets 1 mg and 5 mg for oral useOsilodrostat tablets 1 mg and 5 mg for oral use.During the 18-week titration phase, the dose of the medication will be titrated every 3 weeks based on the cortisolaemic and clinical response to treatment. An independent endocrinologist titration committee will be applied to provide recommendations on dose-titration based on biochemical and clinical response. At the end of the 18-week dose titration phase, participants will enter a 12-week dose maintenance phase, which is also blinded. They will continue with the dose they were receiving at the end of the dose titration phase, unless there is a need to down-titrate or to stop the study medication for safety purposes.
DRUGPlacebo
matching placebo
Sponsors
RECORDATI GROUP
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female ≥ 18 years of age 2. Able to provide and have provided signed written informed consent prior to study participation 3. Diagnosis of endogenous Cushing's Syndrome 4. mUFC values from two 24h urinary collections \> ULN and ≤ 2x ULN 5. Participants with uncontrolled hypertension on stable doses of BP lowering medications (for at least 4 weeks); qualifying BP measurements by ABPM taken prior to randomisation defined as: Average of 24h ABPM SBP ≥ 135 or DBP ≥ 85 mmHg 6. Participants under glucocorticoid replacement therapy can be recruited only if this therapy has been already stopped for at least seven days or 5 half-lives prior to screening, whichever was longer 7. Not taking any drug therapy for CS. The following minimum periods without these medications need to be completed before baseline assessments: 1. Steroidogenesis inhibitors (e.g. ketoconazole, metyrapone): 1 week 2. Mifepristone: 3 weeks 3. SC Pasireotide: 1 week 4. Pasireotide LAR: 3 months 5. Cabergoline: 4 weeks 8. Able to take oral medication and be willing to comply with the requirements of the study
Exclusion criteria
1. Previously treated with osilodrostat less than 12 weeks prior to start of screening 2. Known hypersensitivity to osilodrostat 3. Presence of any severe and/or uncontrolled medical condition or other conditions that could affect participation in the study 4. Participants who are scheduled for a surgery to treat CS within 32 weeks of randomisation to the study drug 5. Presence of a known long term history of both hypertension and diabetes (defined as both hypertension and diabetes diagnosed \>10 years prior to the initial diagnosis of endogenous CS) 6. History of cyclic Cushing's Syndrome with fluctuating clinical manifestations 7. Participants with pseudo-CS 8. Participants with compression of the optic chiasm due to a macroadenoma or participants at high risk of compression of the optic chiasm (tumour within 2 mm of optic chiasm) 9. Pituitary radiation therapy within 3 years of screening 10. Ectopic ACTH syndrome or adrenocortical carcinoma with a life expectancy of \<3 years or receiving chemotherapy 11. Having received prior mitotane treatment 12. Participants who are shift workers or have conditions that can affect the measurement of late night salivary cortisol (LNSC) or the LDDST 13. Poorly controlled diabetes mellitus with a baseline HbA1c \> 10.5% 14. Poorly controlled BP defined as: Average SBP ≥ 170 or average DBP ≥ 110 mmHg as measured by the 24h ABPM 15. Participants who are hypothyroid and not on adequate replacement therapy 16. History of major surgery/surgical therapy for any cause within 1 month before entering the study. 17. Presence of bradycardia and/or QT-related
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To evaluate the efficacy of osilodrostat on the proportion of participants with normalisation of urinary-free cortisol (UFC) | 30 weeks | Proportion of participants with normalisation of the 24h-mUFC (as measured by the mean of the UFC concentrations of two 24-h urine collections ≤1xULN) |
Outcome results
None listed