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    Summary
    EudraCT Number:2017-004647-20
    Sponsor's Protocol Code Number:COR-2017-OLE
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-11-15
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2017-004647-20
    A.3Full title of the trial
    An Open-label Extension Study of Levoketoconazole (2S,4R-ketoconazole) in the Treatment of Endogenous Cushing’s Syndrome
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Assess Levoketoconazole in the Treatment of Endogenous Cushing’s Syndrome
    A.4.1Sponsor's protocol code numberCOR-2017-OLE
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03621280
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCortendo AB
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCortendo AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCortendo AB
    B.5.2Functional name of contact pointClinical Trial Information
    B.5.3 Address:
    B.5.3.1Street Addressc/o TMF Sweden AB. Sergels Torg 12
    B.5.3.2Town/ cityStockholm
    B.5.3.3Post code111 57
    B.5.3.4CountrySweden
    B.5.6E-mailinfo@cortendo.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/12/1012
    D.3 Description of the IMP
    D.3.1Product namelevoketoconazole
    D.3.2Product code COR-003
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNlevoketozonazole
    D.3.9.1CAS number 142128-57-2
    D.3.9.2Current sponsor codeCOR-003
    D.3.9.4EV Substance CodeSUB178316
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Endogenous Cushing´s syndrome (CS)
    E.1.1.1Medical condition in easily understood language
    In this condition patients produce an excessive level of a steroid hormone known as cortisol
    E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10011657
    E.1.2Term Cushings syndrome
    E.1.2System Organ Class 100000004860
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess long-term safety and efficacy durability of levoketoconazole as chronic treatment for endogenous Cushing’s Syndrome (CS).
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal 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 procedures.
    E.4Principal 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 medication that cannot be discontinued safely and washed out completely prior to the Baseline Visit, including but not limited to the following:
    - Drugs used to treat Cushing’s Syndrome;
    - Weight loss medications (prescription or over the counter);
    - Acetaminophen (paracetamol) above 2 g total daily dose;
    - Strong inducers or inhibitors of CYP3A4 enzyme system that may interfere with the metabolism of levoketoconazole and cannot be discontinued prior to first dose;
    - Herbal preparations: St John’s Wort, echinacea, gingko, goldenseal, yohimbe, red yeast rice, danshen, Silybum marianum, Asian ginseng, Schissandra sphenanthera, shankhapushpi, and Asian herb mixture (Xiao chai hu tang and Saiboku-to);
    - Topical or inhaled corticosteroids (other than low potency products to be discussed with Medical Monitor first);
    - Carbamazepine;
    - Drugs that pose unacceptable risk due to overlapping or exaggerated toxicities or pharmacological action due to presumed PK or pharmacodynamic interactions with levoketoconazole.
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(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.
    E.5.2Secondary 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Each regular visit (every 3 months) including the final study visit.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA32
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Bulgaria
    Denmark
    France
    Greece
    Hungary
    Israel
    Italy
    Netherlands
    Poland
    Romania
    Spain
    Turkey
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    1 week after LVLS (Safety Follow-Up Call to be conducted 1 week following the Final Study Visit)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 38
    F.4.2.2In the whole clinical trial 60
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-01-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-19
    P. End of Trial
    P.End of Trial StatusOngoing
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