Endogenous Cushing´s syndrome (CS) MedDRA version: 20.0 Level: LLT Classification code 10011657 Term: Cushings syndrome System Organ Class: 100000004860
Conditions
Interventions
Product Name: levoketoconazole
Product Code: COR-003
Pharmaceutical Form: Tablet
INN or Proposed INN: levoketozonazole
CAS Number: 14212
Sponsors
Cortendo AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: To be eligible for participation in this study subjects for whom the investigator believes long-term use of levoketoconazole may be beneficial must meet ONE of the following criteria: 1. Completed the Extended Evaluation Phase of Study COR-2012-01 (i.e. M12). 2. Completed the Restoration Phase of Study COR-2017-01 (i.e. RES2). NOTE: Subjects meeting criteria 1 or 2 above who have had a break in therapy may be eligible only after discussion with the Medical Monitor. If eligible, such subjects should resume levoketoconazole at or below the prior therapeutic dose at the discretion of the Investigator. Prior to resuming treatment with levoketoconazole, other therapies for Cushing’s syndrome must undergo an appropriate washout period, with minimum durations as follows: - 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 (immediate release) or short-acting pasireotide: 1 week; - Mifepristone (RU 486, KORLYM®): 4 weeks; - Megestrol acetate or medroxyprogesterone acetate (and selected other synthetic progestins): 6 weeks. 3. Currently in a named patient program or other Expanded Access Program receiving levoketoconazole. 4. Were levoketoconazole-naïve prior to entry and received early rescue therapy with open-label levoketoconazole in Study COR-2017-01. 5. Were levoketoconazole-naïve prior to entry and were enrolled in Study COR-2017-01 in the Dose Titration and Maintenance Phase when randomization was closed. (NOTE: Such subjects may continue in Study COR-2017-01 until a therapeutic dose has been established or until the end of the Dose Titration and Maintenance Phase, whichever comes first.) In addition, subjects must meet ALL the following criteria: 1. Willing to participate and 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. 2. A female is eligible to enter and participate in the study if she is: - Postmenopausal, defined as age 50 years or older with amenorrhea for more than 1 year or any age with serum follicle stimulating hormone (FSH) at least 23 mIU/mL and estradiol no more than 40 pg/mL (140 pmol/L) (NOTE: laboratory values obtained during COR-2012-01 or COR-2017-01 protocol will be utilized). OR - Surgically sterile with documented hysterectomy and/or bilateral oophorectomy or tubal ligation. OR - Of child-bearing potential and agrees to use a highly effective method of birth control while participating in the study and for 30 days after the last dose of levoketoconazole. Abstinence is considered acceptable birth control if routinely practiced. Fertile men must also agree to use a highly effective method of birth control while participating in the study and for 90 days after the last dose of levoketoconazole. Abstinence is considered acceptable birth control if routinely practiced. 3. Able to comprehend and comply with pro
Exclusion criteria
Exclusion criteria: Subjects will not be eligible for participation in the study if ANY of the following criteria are met: 1. Discontinued levoketoconazole while participating in Study COR-2012-01 or Study COR-2017-01 or a named patient program or other Expanded Access program, due to safety or tolerability concerns or lack of efficacy. 2. Pregnant, lactating or intend to conceive while receiving levoketoconazole. 3. Have a medical condition or other circumstances that, in the opinion of the Investigator, might interfere with the subject’s participation or pose unacceptable risk to the subject. 4. Scheduled for surgical for treatment of CS or received surgical treatment of CS within the 6 weeks prior to Screening. 5. Had non-CS major surgery within 4 weeks prior to Screening. 6. Treated with mitotane within 6 months prior to 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. QTc interval greater than 470 msec via central-reader interpretation during Screening. 9. Clinically significant abnormality in 12-lead electrocardiogram (ECG) during the Screening requiring medical intervention (may be eligible once stable, to be determine case by case). 10. Clinical or radiological signs of compression of the optic chiasm newly apparent since enrolling in a parent study. 11. Liver safety tests during the Screening Phase as follows: - ALT and/or AST above 3X ULN (NOTE: transaminase values up to 5X ULN may be allowed on an exceptional basis for subjects who have exhibited stable values for at least 3 months) - AP or TBN above 2X ULN. Subjects with isolated indirect TBN up to 3X ULN that are presumed to have Gilbert’s syndrome may be enrolled if all other liver safety tests are within normal levels. 12. Decreased renal function as defined by eGFR below 40 mL/min/1.73 m2, using MDRD equation for eGFR 13. Serum potassium below 3.9 mEq/L (may be supplemented to achieve 3.9 mEq/L or above). 14. 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. 15. Abused alcohol or drugs since enrolling in a parent study (in the Investigator’s opinion). 16. Currently participating in another study or has received any investigational treatment (drug, biological agent or device) other than levoketoconazole, within prior 30 days of the Screening visit or five half-lives of treatment, whichever is longer. 17. Current use of any H2-receptor antagonists, proton-pump inhibitors, or sucralfate (all inhibit absorption of levoketoconazole; subjects may be allowed to enroll after washout). [NOTE: A list of acceptable oral antacids will be provided; if used, antacids must be ingested at least 2 hours after dosing of levoketoconazole.] 18. Current use of any prohibited concomitant medicati
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess long-term safety and efficacy durability of levoketoconazole as chronic treatment for endogenous Cushing’s Syndrome (CS).;Secondary Objective: Not applicable; Primary end point(s): Exploratory Efficacy Endpoints: - Proportions of subjects with mean urinary free cortisol (mUFC): 1) Less or equal to the upper limit of normal (ULN) of the reference range; 2) Above the ULN to 1.5X the ULN; and 3) Above 1.5X the ULN; - Changes from Baseline in markers of cortisol including mUFC and late night salivary cortisol (LNSC); - Proportion of subjects with LNSC above the ULN of the reference range; - Changes from Baseline in Clinical Signs and Symptoms of CS, health-related quality of life (QoL), and symptoms of depression; - Changes from Baseline in biomarkers of CS comorbidities (fasting blood glucose [FBG], fasting insulin, homeostatic model assessment-insulin resistance [HOMAIR], 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]); - Frequency of usage and changes from Baseline in frequency of usage of antidiabetic, anti-cholesterol and anti-hypertensive therapies; - Compliance (adherence) and persistence with therapy per tablet counts. ; Timepoint(s) of evaluation of this end point: Each regular visit (every 3 months) including the final study visit. Changes from Baseline for efficacy evaluations, Baseline will be either or both of: - Open-label extension (OLE) study Baseline; - The original parent study COR-2012-01 [SONICS] or COR-2017-01 [LOGICS]) Baseline; With the choice of Baseline described in the Statistical Analysis Plan for each endpoint/analysis. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Safety endpoints: Safety will be assessed by incidence and severity of Adverse Events (AEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) as well as by physical examinations, safety laboratory panels (including Adrenocorticotropic Hormone [ACTH], liver function tests [LFTs], blood chemistry, hematology), electrocardiograms (ECGs) (to include assessment of the QTc interval), vital signs and pituitary Magnetic Resonance Imaging (MRI) for subjects with history of a pituitary tumor. ;Timepoint(s) of evaluation of this end point: Each regular visit (every 3 months) including the final study visit. | — |
Countries
Bulgaria, Denmark, France, Greece, Hungary, Israel, Italy, Netherlands, Poland, Romania, Spain, Turkey, United States
Contacts
Public ContactClinical Trial Information
Cortendo AB
Outcome results
None listed