Cushing's Syndrome
Conditions
Interventions
CORT125134, administered to fasting patients orally as capsules containing 50
mg of CORT125134:
Group 1: 100 mg/day for 4 weeks, then 150 mg/day for 4 weeks, then 200 mg/day
for 4 weeks
Group 2: 25
CORT125134-451
Endogenous Cushing's Syndrome
High blood pressure
Type 2 diabetes
Sponsors
Corcept Therapeutics Incorporated
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: Patients must meet all of the following inclusion criteria before study entry to be eligible for enrollment into the study: 1. Is a male or female adult, 18*80 years of age 2. Has a diagnosis of endogenous Cushing*s syndrome confirmed by: At least two of the following test criteria: * Urinary free cortisol above the upper limit of normal (ULN) (50.0 *g/24 h) in at least 2, and up to 4, complete 24 hour collections within 3 weeks prior to Day 1 (baseline) * Late-night salivary cortisol above the ULN (at least 2, and up to 4, collections using a salivette) within 3 weeks prior to Day 1 (baseline) * Lack of cortisol suppression (>1.8 *g/dL serum cortisol) on either 1 mg overnight or 2-mg 48 hour dexamethasone suppression testing during screening or within 12 weeks before the ICF is signed. And At least two of the following clinical signs and symptoms of Cushing*s syndrome: * Facial characteristics of a Cushingoid appearance (moon facies, dorsocervical fat pad, plethora) * Increased body weight or central obesity * Proximal muscle weakness * Low bone mass (dual energy X-ray absorptiometry [DXA] T 5 µg/dL serum cortisol) on either 1-mg overnight or 2-mg 48 hour dexamethasone suppression testing during screening * Low or suppressed ACTH (126 mg/dL and a 2-hour oral glucose tolerance test (oGTT) result for plasma glucose *200 mg/dL at 2 hours * Has impaired glucose tolerance (2-hour oGTT result for plasma glucose in the range of *140 mg/dL to <200 mg/dL) * Has hypertension (mean systolic BP of 130*170 mmHg and/or a mean diastolic BP of 85*110 mmHg) based on 24 hour ambulatory BP measurement 5. If taking antidiabetic medication, is on a stable dose (ie, cannot start new medication or change dose within 4 weeks prior to the first dose of study drug) 6. If taking antihypertensive medication, is on a stable dose (ie, cannot start new medication or change dose within 4 weeks prior to the screening ambulatory BP measurement) 7. Has potassium within the normal range (3.5*5
Exclusion criteria
Exclusion criteria: Patients who meet any of the following exclusion criteria will not be eligible to participate in the study: 1. Has a non-endogenous source of hypercortisolemia 2. Has pseudo-Cushing*s syndrome. Patients with known or suspected pseudo-Cushing*s syndrome based on medical history (such as patients with severe obesity, major depression, or a history of alcoholism) should undergo a dexamethasone-CRH/DDAVP stimulation test to rule-in or rule-out this possibility. 3. Has uncontrolled, clinically significant hypothyroidism or hyperthyroidism 4. Has poorly controlled hypertension, defined as systolic BP >170 mmHg or diastolic BP >110 mmHg at screening 5. Has Stage *4 renal failure (ie, glomerular filtration rate *29 mL/min) 6. Has elevated total bilirubin >1.5×ULN or elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3×ULN 7. For patients with diabetes or abnormal oGTT at screening: has glycated hemoglobin (HbA1c) of >12% within 3 months of first dose of study drug 8. Has a screening hemoglobin level of 450 ms for males and >470 ms for females (using Fridericia*s correction) in the presence of a normal QRS interval (QRS <120 ms) or a history of additional risk factors for torsades de pointes 11. Is currently receiving chemotherapy for a tumor related to Cushing*s syndrome 12. Had radiation therapy for Cushing*s syndrome-related tumor within 1 year of screening period 13. Is planning surgery or radiation therapy for Cushing*s syndrome-related tumor during the study 14. Has used or plans to use any of the following treatments for Cushing*s syndrome, as specified: * Adrenostatic medications: metyrapone, ketoconazole, fluconazole, aminoglutethimide, or etomidate from 4 weeks prior to baseline (Day 1) through the follow-up visit * Adrenolytic medications: o In Group 1, any patients taking mitotane o In Group 2 only, patients with adrenocortical carcinomas taking mitotane whose dose has not been stable for at least 2 months prior to baseline (Day 1) or in whom increases in the mitotane dosage are expected through the end of dosing * Neuromodulator drugs that act at the hypothalamic-pituitary level: serotonin antagonists (cyproheptadine, ketanserin, retanserin), dopamine agonists (bromocriptine, cabergoline), gamma-aminobutyric acid agonists (sodium valproate), and somatostatin receptor ligands (octreotide long-acting release [LAR], pasireotide LAR, lanreotide) from 8 weeks before baseline (Day 1) through the follow-up visit. Use of short-acting somatostatin analogs (octreotide, pasireotide) from 4 weeks prior to baseline (Day 1) through the follow-up visit. * Mifepristone, from 6 weeks before baseline (Day 1) through the follow-up visit 15. Has started or increased (or plans to start or increase) the dose of an antidepressant medication (eg, selective serotonin reuptake inhibitors or tricyclic compound) from 6 weeks before baseline (Day 1) through the end of the study dosing period 16. Has started or increased (or plans to start or increase) the dose of a lipid-lowering drug from 4 weeks before baseline (Day 1) through the follow-up visit 17. Is lactating 18. Has an acute or unstable medical pro
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Key efficacy assessments * Oral glucose tolerance test (impaired glucose tolerance/diabetes subgroup only) * Ambulatory BP measurement (hypertension subgroup only) | — |
Secondary
| Measure | Time frame |
|---|---|
| Exploratory efficacy assessments * Physician*s Global Assessment * HbA1c * Fructosamine * Adiponectin * 24-hour urinary free cortisol (UFC) with creatinine * Late-night salivary cortisol * Body weight, waist circumference * Beck Depression Inventory (BDI-II), Trail Making Test, CushingQoL * Lipid panel * Sit-to-stand test * Sex hormone levels * Menstrual cycle characterization (premenopausal women not on hormonal birth control) * Coagulation tests * Glucocorticoid receptor (GR) biomarker tests * Bone markers (serum bone alkaline phosphatase, osteocalcin, urine N telopeptides of type 1 collagen [NTx], calcium from 24-hour UFC) * Hypothalamic-pituitary-adrenal (HPA) axis markers, including plasma ACTH and serum cortisol concentrations * ACTH precursors * High-sensitivity C-reactive protein concentrations * 24-hour urine calcium and sodium * Insulin-like growth factor (IGF-1) * Thyroid function tests Pharmacokinetics Blood levels of CORT125134 and metabolites will be measured predose and at 1, 2, 4, 6, and 8 hours postdose at Weeks 2, 6, and 10, and predose only at Weeks 4, 8, and 12/early termination (ET). Safety Safety will be assessed by physical examination findings, vital signs, ECG results, pregnancy tests, clinical laboratory test results (hematology and chemistry panels), adverse events (AEs), and concomitant medications. | — |
Countries
Hungary, Italy, Netherlands, United Kingdom, United States of America
Outcome results
None listed