Endogenous Cushing´s syndrome (CS) MedDRA version: 20.0 Level: LLT Classification code 10011657 Term: Cushings syndrome System Organ Class: 100000004860
Conditions
Sponsors
Cortendo AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion Criteria for Specified SONICS-Completers: SONICS-completers, including those receiving open-label treatment after SONICS as part of an Expanded Access Program (EAP) or OLE study, whose completion of the M12 visit occurred not more than 6 months prior to the anticipated Randomization Visit (RW0), may be eligible for the study if the following two inclusion criteria are met: 1. Completed the final SONICS visit (M12) and have demonstrated maintenance of clinical response (partial or complete) on a stable Therapeutic Dose of levoketoconazole for at least 12 weeks prior to study entry (Visit RW0) 2. Able and willing 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 Inclusion Criteria for All Others: The following categories of potential subjects, categorized by prior use of levoketoconazole, may be eligible if the following 11 inclusion criteria are all met: • Naïve to levoketoconazole (defined as having never participated in SONICS); • Completers of SONICS visit M12 more than 6 months prior to the expected RW0 visit of the current study; • Completers of SONICS visit M12 within the 6 months prior to the expected RW0 visit who have not been receiving a stable Therapeutic Dose of levoketoconazole for at least 12 weeks prior to the start of screening. 1. Male or female and at least 18 years of age. 2. Able and willing to provide written informed consent 3. Confirmed newly diagnosed, persistent or recurrent endogenous Cushing’s syndrome of any etiology, except secondary to malignancy (including pituitary or adrenal carcinoma). Persistence will not be considered confirmed until 6 weeks or more post-surgery 4. Elevated mean 24 hour UFC levels at least 1.5X ULN of the normative range of the study’s central laboratory assay and from a minimum of three measurements from adequately collected urine; the study’s central laboratory must be used for all qualifying measurements. 5. Presence of abnormal values from at least one of these two diagnostic tests (discrepancies between test findings will not be investigated nor considered exclusionary): • Abnormal Dexamethasone Suppression Test (DST): Elevated 8 AM blood cortisol at least 1.8 mcg/dL (50 nmol/L) after 1 mg dexamethasone orally at 11 PM the evening prior with concurrent dexamethasone blood concentration greater than 5.6 nmol/liter (220 ng/dL) (results from within the 2 months prior to start of Screening or newly tested with results available by the Baseline Visit [TM0]) OR • Elevated LNSC concentrations (at least two measurements) each greater than the ULN of the study’s central laboratory normative range; the study’s test kit and lab must be used for all qualifying measurements. 6. Non-candidates for CS-specific surgery, refuse surgery or surgery will be delayed until after study completion and agree to complete this study prior to surgery. 7. If post-surgical for CS-specific surgery, then no significant post operative sequelae remain and the risk of such sequelae is considered negligible. 8. Agree to the following minimum washout periods prior to the Baseline Visit (TM0) (as applicable): • Ketoconazole or metyrapone: 2 weeks; • Dopamine agonists: bromocriptine (2 weeks), cabergoline (8 weeks); • Octreotide acetate LAR, lanreotide Autogel®, pasireotide LAR: 12 weeks; • Lanreotide SR: 8 weeks; • Octreotide acetate (immedi
Exclusion criteria
Exclusion criteria: Subjects will be excluded from the study if ANY of the following criteria are met: 1. Enrolled in SONICS but have not completed SONICS through Visit M12 2. Pseudo-Cushing’s syndrome based on assessment of the Investigator 3. Cyclic Cushing’s syndrome with multi-week periods of apparent spontaneous CS remission 4. Non-endogenous source of hypercortisolism, including pharmacological corticosteroids or ACTH 5. Radiotherapy of any modality directed against the source of hypercortisolism within the last 5 years 6. Treatment with mitotane within 6 months of enrollment 7. History of malignancy, including adrenal or pituitary carcinomas (other than low risk, well-differentiated carcinomas of thyroid, breast or prostate that are very unlikely to require further treatment in the opinion of the treating physician, or squamous cell or basal cell carcinoma of the skin) 8. Clinical or radiological signs of compression of the optic chiasm 9. Major surgery within 1 month of Screening (or within 6 weeks for pituitary surgery) 10. Clinically significant abnormality in 12-lead ECG during the Screening Phase requiring medical intervention 11. QTc interval above 470 msec during the Screening Phase 12. History of Torsades des Pointes, ventricular tachycardia, ventricular fibrillation, history of prolonged QT syndrome 13. Use of medications associated with possible, probable, or definite QT/QTc prolongation 14. Pre-existing hepatic disease 15. Hepatitis B surface antigen (HbsAg) or hepatitis C-positive 16. Human immunodeficiency virus (HIV)-positive. 17. History of symptomatic cholelithiasis with intact gallbladder 18. History of pancreatitis 19. Liver safety tests during the Screening Phase as follows: - ALT and/or AST above 3X ULN - Alkaline phosphatase or TBN above 2X ULN Subjects with isolated indirect TBN up to 3X ULN are presumed to have Gilbert’s syndrome and may be enrolled if all other liver safety tests are within normal levels 20. History of documented or suspected drug-induced liver injury to ketoconazole or any other azole drug 21. Serum potassium below 3.0 mEq/L 22 Abnormal free thyroxine (FT4), unless subsequently corrected and stable for at least 4 weeks. Subjects with thyroid-stimulating hormone (TSH) less than the lower limit of normal (LLN) and normal FT4 are potentially eligible without intervention 23. History of persistent uncontrolled hypertension 24. Hypercholesterolemia currently treated with atorvastatin, lovastatin or simvastatin and unwilling or unable to change to alternative therapy with: pravastatin, fluvastatin, pitavastatin or rosuvastatin (must switch statin at least 2 weeks prior to dosing) or another allowed therapy. 25. More than one hospitalization for hyperglycemia or complication of diabetes, or uncontrolled diabetic patients with HbA1c>8% during the last 12 months 26. Decreased renal function as defined by eGFR below 40 mL/min/1.73 m2, using MDRD equation for eGFR 27. Pregnant or lactating 28. Body habitus preventing repeated venipuncture as required by protocol 29. Any other clinically significant medical condition, as determined by the Investigator that precludes enrollment and participation in the study through completion, including conditions that would preclude the subject from being able to follow instructions or perform necessary procedures 30. History of alcohol or drug abuse in the 6-month period prior to Screening 31. Currently participating in another study or has rec
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine the effect of withdrawing to placebo versus continuing treatment with levoketoconazole on the cortisol therapeutic response previously established during open-label levoketoconazole therapy.;Secondary Objective: To compare the effects of levoketoconazole with placebo on: - cortisol status during Randomized Withdrawal and Restoration Phases; - changes in clinical signs & symptoms of Cushing’s syndrome (CS); - changes in biomarkers of CS comorbidities; - To assess the safety and tolerability of levoketoconazole; - To evaluate the population pharmacokinetics of levoketoconazole in subjects with CS NOTE: Secondary Objectives 4 & 5 are not subjects of hypothesis tests Exploratory Objectives: 1. To assess changes in anti-diabetic, anti-cholesterol, anti-hypertensive, and chronic anti-inflammatory therapies; 2. To describe the effects & durations of levoketoconazole action with respect to cortisol status, health-related quality of life, and symptoms of depression 3. To describe the dose-response relationship of levoketoconazole with respect to safety and tolerability 4. To describe the effects of levoketoconazole on glucose tolerance among subjects with impaired fasting glucose (IFG).;Primary end point(s): Proportion of subjects with loss of therapeutic response to levoketoconazole upon withdrawing to placebo compared with the proportion of subjects with loss of therapeutic response upon continuing treatment with levoketoconazole. Loss of therapeutic response (i.e. relapse) is inferred based on mUFC from of three 24-hour urinary free cortisol (UFC) measurements obtained at any visit from second through final Randomized Withdrawal Phase visits (RW1 through RW5 inclusive) when: (1) mUFC is above 1.5X the ULN of the central laboratory’s reference range, OR (2) mUFC is more than 40% above the baseline (RW0) value, if the RW0 value is at or above the ULN (i.e. =1.0X ULN) , OR (3) an early rescue criterion is met, necessitating open-label ther | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: 1: at all post-Baseline visits through the final study visit (RES2) 2: at RES2 3: at all post-Baseline visits through the final study visit (RES2) 4: at all post-Baseline visits through the final study visit (RES2) 5, 6 and 7: along the study 8: all post-Baseline visits 9: from baseline till first time of loss of response 10: from RES1 till first normalization of mUFC 11: from RES1 till first normalization of LNSC 12: at RES2 13: at all post-Baseline visits through the final study visit (RES2) 14: at all post-Baseline visits through the final study visit (RES2) 15: along the study 16: at all post-Baseline visits through the final study visit (RES2) 17: along the study 18 along the study;Secondary end point(s): 1. Changes from Baseline (RW0) in mUFC and LNSC at all post-Baseline visits with these assessments through the final study visit (RES2)—applies to Secondary Objective 1; 2. Proportion of subjects with normalization of mUFC at RES2—applies to Secondary Objective 1; 3. Changes from Baseline (RW0) in clinical signs and symptoms of CS at all post Baseline visits with these assessments through the final study visit (RES2)—applies to Secondary Objective 2; 4. Changes from Baseline (RW0) in biomarkers of CS comorbidities (fasting glucose, fasting insulin, homeostatic model assessment-insulin resistance [HOMA-IR], hemoglobin A1c (HbA1c), blood pressure, total cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), high-sensitivity C-reactive protein (hsCRP) at all post-Baseline visits with these measurements through the final study visit (RES2)—applies to Secondary Objective 3; 5. Incidence and severity of adverse events (AEs), particularly adverse events of special interest (AESI) during levoketoconazole open-label therapy in the Dose Titration and Maintenance Phase (levoketoconazole-naïve cohort) and during blinded therapy in the Randomized With | — |
Countries
Bulgaria, Canada, Denmark, France, Greece, Hungary, Israel, Italy, Netherlands, Poland, Romania, Spain, United States
Contacts
Public ContactClinical Trial Information
Cortendo AB
Outcome results
None listed