Endogenous Cushing's syndrome (CS) or Cushing's disease MedDRA version: 19.0 Level: LLT Classification code 10011657 Term: Cushings syndrome System Organ Class: 100000004860
Conditions
Interventions
Product Name: COR-003
Pharmaceutical Form: Coated tablet
INN or Proposed INN: Not available
CAS Number: 65277-42-I
Current Sponsor code:
Sponsors
Cortendo AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female =18 years of age 2. Able to provide written informed consent prior to any study procedures being performed; eligible subjects must be able to understand the informed consent form prior to inclusion into the study. 3. Confirmed diagnosis of newly diagnosed, persistent or recurrent CD or endogenous CS of other etiology if subjects are not candidates for surgery or radiotherapy within the 18 months after enrollment. Previous medical records will be collected and used to support the diagnosis of CD or endogenous CS of other etiology, including the following etiologies: • Ectopic ACTH secretion, i.e. ACTH not of pituitary origin • Ectopic corticotropin-releasing hormone (CRH) secretion • Adrenal-dependent CS (i.e. adrenal adenoma (NOT carcinoma), adrenal hyperplasia, etc.) • Etiology unknown In the absence of pathological or post-surgical confirmation of the diagnosis of CD (i.e. documented adrenal insufficiency post-adenomectomy or hypophysectomy, which will be considered diagnostic). The following historical evidence will be considered satisfactory to establish the diagnosis of CD: • Plasma corticotropin (ACTH) level >20 pg/mL (4.5 pmol/L) or greater (Note: ACTH =5 pg/mL (1.1 pmol/L) and =20 pg/mL will generally suffice only if accompanied by either a positive CRH stimulation test or DST or combined CRH-DST) PLUS one of the diagnostic strategies described below based on pituitary MRI/computed tomography (CT) findings (Note: pituitary imaging preceding the original diagnosis is a requirement for eligibility): • For tumors =6 mm by imaging: - Inferior petrosal sinus sampled (IPSS) ACTH central:plasma gradient =2 before CRH or =3 after CRH, OR if IPSS was not done then: - Positive ACTH and/or cortisol response to CRH/desmopressin or combined CRH-desmopressin stimulation plus high-dose (8 mg) dexamethasone suppression of plasma cortisol, ideally on more than one occasion, performed and interpreted according to internationally recognized standards of diagnosis - In the absence of IPPS and the combination of tests described, an individual might be eligible if CD was otherwise confirmed via adequate testing. Such cases must be discussed with and explicitly approved by the Medical Monitor, and the specific diagnostic criteria used to establish the diagnosis of CD must be documented. • For tumors <6 mm or not visible by MRI: - IPSS with ACTH central:plasma gradient =2 before CRH or =3 after CRH - In the absence of IPSS, an individual might be eligible if CD was otherwise confirmed via adequate testing. Such cases must be discussed with and explicitly approved by the Medical Monitor, and the specific diagnostic criteria used to establish the diagnosis of CD must be documented. 4. Regardless of the etiology of endogenous CS, subjects MUST have elevated mean 24-hour UFC levels =1.5X ULN based on the normative range of the central lab assay and on a minimum of four measurements from adequately collected urine. Urine will ideally be collected on sequential days. 5. In addition to elevated mean UFC, presence of abnormal values from one of the following tests: • Abnormal DST: Elevated 8 AM serum cortisol =1.8 µg/dL (50 nmo
Exclusion criteria
Exclusion criteria: 1. Subjects with Pseudo-CS based on assessment of the Investigator 2. Subjects with cyclic CS based on assessment of the investigator 3. Subjects with a non-endogenous source of hypercortisolism such as exogenous source of glucocorticoids or therapeutic use of ACTH. 4. Known inherited syndrome as the cause of hypercortisolism, including but not limited to multiple endocrine neoplasia Type 1, McCune Albright Syndrome and Carney Complex 5. Subjects with adrenal carcinoma 6. History of malignancy, other than thyroid, early stage prostate, squamous cell and basal cell carcinoma, within 3 years prior to the Screening Phase. Subjects with history of such allowed carcinoma must have a life expectancy of >18 months and must be considered medically stable. Subjects with early stage prostate cancer undergoing no treatment due to low grade potential may be enrolled 7. Clinical or radiological signs of compression of the optic chiasm 8. Major surgery within 1 month prior to enrollment 9. Subjects with clinically significant abnormality in 12-lead ECGs during the Screening Phase needing medical intervention 10. Subjects with QTc interval of >470 msec during the Screening Phase 11. Subjects with a history of Torsades des Pointes, or ventricular tachycardia, or ventricular fibrillation, or history of prolonged QT syndrome (including family history), or use of medications resulting in QT/QTc prolongation, or hypokalemia 3 X ULN • Total bilirubin (TBN) >2 X ULN If all LFTs are within normal limits and TBN is elevated, examination of direct and indirect bilirubin may be conducted. Subjects with isolated indirect TBN up to 3X ULN are presumed to have Gilbert’s syndrome and may be enrolled if all other LFTs are within normal levels 16. History of documented or suspected drug-induced liver injury requiring drug discontinuation of ketoconazole or any azole antifungals 17. Pregnant or lactating women 18. HIV positive 19. History of persistent uncontrolled hypertension (>180/120 mmHg) despite medical intervention. 20. Subjects with hypercholesterolemia currently treated with atorvastatin, lovastatin or simvastatin and not willing or unable to change to alternative therapies i.e. pravastatin, fluvastatin, or rosuvastatin within 2 weeks of start of the Screening Phase. 21. Body habitus preventing repeated venipuncture as required by protocol. 22. Subject is currently in another study or has received any investigational treatment (drug, biological agent or device) within 30 days or five half-lives of treatment, whichever is longer. 23. Repeated hospitalization for hyperglycemia or for any complication of hyperglycemia and diabetes during the last 12 months
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the clinical responder rate, defined as the proportion of subjects with normal UFC after 6 months of treatment with COR-003 in the Maintenance Phase without dose increase, and to evaluate the range of effective doses in subjects with various levels of hypercortisolism.; Secondary Objective: • To identify the proportion of subjects with clinical response, defined as reduction in mean 24-hour UFC levels to below or equal to the upper limit of normal (= ULN) after each month of treatment with COR-003 without a dose increase during the Maintenance Phase; • To identify the proportion of subjects with complete or partial response, defined as =50% reduction of 24-hour UFC levels from Baseline after each of the 6 months of treatment with COR-003 without a dose increase during the Maintenance Phase; • To characterize changes in 24-hour UFC levels from Baseline during the 6 months of treatment with COR-003 in the Maintenance Phase regardless of dose increases; • To characterize shifts in normality for 24-hour UFC levels from Baseline during the 6 months of treatment with COR-003 in the Maintenance Phase regardless of dose increases; For all other secondary objectives, please refer to the protocol. ;Primary end point(s): Proportion of subjects with response to COR-003, defined as reduction in mean 24-hour UFC levels to below or equal to the upper limit of normal (= ULN) following 6 months of Maintenance Phase therapy without a dose increase during that phase, summarized by Maintenance Phase dose level and overall.;Timepoint(s) of evaluation of this end point: Following 6 months of maintenance phase therapy | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Proportion of subjects with clinical response to COR-003, defined as mean UFC level = ULN, to be determined after 1, 2, 3, 4 and 5 months of dosing without a dose increase in the Maintenance Phase; • Proportion of subjects with complete or partial response to COR-003, defined as mean UFC level = 50% reduction from Baseline after 1, 2, 3, 4, 5 and 6 months of dosing without a dose increase in the Maintenance Phase; • Change and percentage change from Baseline in mean 24-hour UFC levels after 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase regardless of dose increases; • Shift in UFC normality categories from Baseline to 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase regardless of dose increases; • Change and percentage change from Baseline in serum and late night salivary cortisol levels after 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase; • Changes from Baseline in Clinical Signs and Symptoms of CS after 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase; • Changes from Baseline in the QoL measures obtained from the Cushing QoL questionnaire and the severity of depression obtained from the Beck’s Depression Inventory II after 3 and 6 months of dosing in the Maintenance Phase; • Change from Baseline in CS comorbidities biomarkers (fasting glucose, hemoglobin A1C [HbA1c], systolic blood pressure [SBP], diastolic blood pressure [DBP], total cholesterol, low and high density lipoproteins [LDL, HDL, respectively], and body weight) after 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase; • Changes from Baseline for oral glucose tolerance test (OGTT) (pre-diabetics only) and spot albumin/creatinine ratio as a measure of microalbuminuria (only if abnormal at Baseline) after 3 and 6 months of dosing in the Maintenance Phase; • Changes from B | — |
Countries
Belgium, Bulgaria, Canada, Czech Republic, Denmark, France, Georgia, Germany, Hungary, Israel, Italy, Netherlands, Poland, Romania, Serbia, Spain, Sweden, Switzerland, Turkey, United Kingdom, United States
Contacts
Public ContactClinical Trial Information
Cortendo AB
Outcome results
None listed