A double-blind, randomised, 30-week placebo-controlled phase IV study to assess the efficacy and safety of osilodrostat in patients with hypertension caused by hypercortisolaemia due to Cushing’s Syndrome

Condition studied

Cushing's syndrome

Investigational medicinal product(s)

Eligibility

Primary endpoint

Normalization status for each participant at Week 30 of treatment with osilodrostat or placebo, based on the mean of UFC concentrations from two 24hour urine collections, with normalization defined as ≤1× the upper limit of normal (ULN).

Endpoint detail

Endpoint for key secondary objective: BP responder status for each participant (response is defined as ≥5 mmHg reduction in mean SBP and/or DBP as measured by ABPM, without worsening of either and without any modification in antihypertensive medications attributable to worsening hypertension) as measured at 30 weeks of treatment with osilodrostat or placebo., Endpoints for secondary objectives: 1. Frequencies and percentages of hypocortisolism-related AEs with osilodrostat or placebo including the following categories: a. Overall hypocortisolism-related AEs b. Glucocorticoid withdrawal syndrome c. Confirmed adrenal insufficiency, 2. In participants with high-risk dysglycaemia at baseline, glycaemic responder status for each participant (defined as: a reduction in AUCglucose during the OGTT by ≥ 25% from baseline, without the addition of or an increase in the dose of glucose lowering medications) at week 30 and week 21 of treatment with osilodrostat or placebo., 3. Body weight responder status for each participant (defined a ≥ 5% decrease from baseline in body weight loss, without the addition of or an increase in the dose of weight lowering medications) at week 30 and week 21 with osilodrostat or placebo, 4. The change from baseline in the SBP as measured by the average 24h- ABPM at week 30 and week 21, and the change over time in sitting SBP with osilodrostat or placebo, 5. In participants with high risk dysglycaemia at baseline the change from baseline in glycaemia at week 30 and week 21 as measured by the glucose Area Under the Curve (AUCglucose) during an OGTT, glycated haemoglobin (HbA1c) and 2-hour post prandial glucose level (PPG). And over time by fasting plasma glucose (FPG) levels with osilodrostat or placebo, 6. Change from baseline over time in body weight with osilodrostat or placebo, 7. Frequencies and percentages of AEs, including AESI, laboratory, and ECG findings with osilodrostat or placebo. Changes from baseline in laboratory values, ECG readings, and in vital signs, 8. Distribution of shifts in categories from baseline to week 30 and week 21 in the American Heart Association (AHA) and American Diabetes Association (ADA) classifications for hypertension and hyperglycaemia with osilodrostat or placebo, 9. Distribution of dose changes (increase, decrease, or no change) and number of blood pressure and glucose lowering medications from baseline to week 30 and week 21 with osilodrostat or placebo, 10. Normalization status of the 24h-UFC for each participant over time osilodrostat or placebo, 11. BP responder status for each participant (defined as ≥ 5mmHg reduction in mean SBP and/or DBP as measured by ABPM - without worsening of either and without any modification in antihypertensive medications attributable to worsening hypertension) as measured at 21 weeks of treatment with osilodrostat or placebo, Endpoints for exploratory objectives: 1. Composite cardiometabolic responder status for each participant (defined as BP responders, or glycaemia responders, or weight responders) at week 30 and week 21 of treatment with osilodrostat or placebo; a participant will be considered a responder if will be responder in at least one of the three responders typologies., 2. Responder status for each participant based on morning (8:00 AM) serum cortisol level ≤ 50 nmol/L (1.8 µg/dL) after a Low Dose Dexamethasone Suppression Test (LDDST) at 30 and 21 weeks of treatment with osilodrostat or placebo, 3. The change from baseline at week 30 and 21 in the diurnal BP pattern as measured by the average daytime and average nighttime SBP and DBP during the 24h-ABPM with osilodrostat or placebo, 4. Change from baseline in the 24h-urine adrenal steroid metabolome at 30 and 21 weeks of treatment with osilodrostat or placebo, 5. The change from baseline at week 30 and week 21 in the DBP as measured by 24h-ABPM and in sitting DBP over time with osilodrostat or placebo, 6. The change from baseline at week 30 and 21 of the morning, noon, afternoon, evening and late-night salivary cortisol and cortisone levels after treatment with osilodrostat or placebo, 7. Changes in HRQoL (Cushing’s QoL and PHQ-9) from baseline to week 30 of treatment with osilodrostat or placebo. And the frequencies and percentages in HRQoL (PGIC) at week 30 of treatment with osilodrostat or placebo, 8. Composite cardiometabolic responder status for each participant (defined as BP responders, and glycaemia responders, and weight responders) at week 30 and week 21 of treatment with osilodrostat or placebo; a participant will be considered a responder if will be responder in all the three responders typologies