Osilodrostat in Patients With Hypertension Caused by Hypercortisolaemia Due to Cushing's Syndrome

Prior treatment

• Previously treated with osilodrostat less than 12 weeks prior to start of screening
• Participants who are scheduled for a surgery to treat CS within 32 weeks of randomisation to the study drug
• 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)
• Participants who have undergone pituitary or adrenal surgery for Cushing's syndrome within 3 months prior to screening.
• Pituitary radiation therapy within 3 years of screening
• Ectopic ACTH syndrome or adrenocortical carcinoma with a life expectancy of \<3 years or receiving chemotherapy
• Having received prior mitotane treatment
• Participants who are hypothyroid and not on adequate replacement therapy
• History of major surgery/surgical therapy for any cause within 4 weeks before entering the study. Participants should have recovered from the surgery and be in good clinical condition before entering the study
• Participation in any clinical investigation within 4 weeks prior to screening or longer if required by local regulation (Use of an investigational drug within 4 weeks prior to dosing)
• Occurrence of any significant acute illness within 3 weeks prior to dosing/randomisation

Other illness

• Known hypersensitivity to osilodrostat
• Presence of any severe and/or uncontrolled medical condition or other conditions that could affect participation in the study
• History of cyclic CS with fluctuating clinical manifestations
• Participants who are shift workers or have conditions that can affect the measurement of late-night salivary cortisol (LNSC) or the LDDST

Lab values

• Poorly controlled diabetes mellitus with a baseline HbA1c \> 10.5%. Participants receiving glucose lowering medications must be on stable doses for at least 4 weeks prior screening.
• Presence of bradycardia and/or QT-related exclusion criteria
• Total bilirubin \> 1.5 x ULN and ALT or AST \> 3 x ULN
• Female participants who are pregnant, intending to become pregnant or breastfeed during the study or lactating, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test

Other

• Participants with pseudo-CS
• 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)
• Women of childbearing potential (WOCBP) who are unwilling to use highly effective contraception methods
• Potentially unreliable or vulnerable participants (e.g. person kept in detention) and those judged by the Investigator to be unsuitable for the study.

• Male or female ≥ 18 years of age
• Able to provide and have provided signed written informed consent prior to study participation
• Diagnosis of endogenous Cushing's Syndrome
• mUFC values from two 24h urinary collections \> ULN and ≤ 2x ULN
• 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
• 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
• Not taking any drug therapy for CS. The following minimum periods without these medications need to be completed before baseline assessments:
  • Steroidogenesis inhibitors (e.g. ketoconazole, metyrapone): 1 week
  • Mifepristone: 3 weeks
  • SC Pasireotide: 1 week
  • Pasireotide LAR: 3 months
  • Cabergoline: 4 weeks
• Able to take oral medication and be willing to comply with the requirements of the study