Treatment for Endogenous Cushing's Syndrome

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2015 by Cortendo AB
Information provided by (Responsible Party):
Cortendo AB Identifier:
First received: April 19, 2013
Last updated: June 25, 2015
Last verified: June 2015

The primary objectives of this study are to evaluate the efficacy of ascending doses of COR-003 in subjects with elevated levels of cortisol due to endogenous Cushing's Syndrome by assessment of reduction in Urinary Free Cortisol (UFC) concentrations and to identify the range of safe and effective doses of COR-003 that reduce mean UFC concentrations ≤ULN (upper limit of normal) of the assay at month 6 of the maintenance phase of dosing without a prior dose increase in that phase.

Condition Intervention Phase
Endogenous Cushing's Syndrome
Drug: COR-003
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open Label Study to Assess the Safety and Efficacy of COR-003 (Levoketoconazole) in the Treatment of Endogenous Cushing's Syndrome

Resource links provided by NLM:

Further study details as provided by Cortendo AB:

Primary Outcome Measures:
  • Reduction in urinary free cortisol in patients with endogenous Cushing's Syndrome. [ Time Frame: 6 months of maintenance phase therapy without a prior dose increase during that phase ] [ Designated as safety issue: No ]
    The response to COR-003 is defined as mean UFC concentration ≤ULN following 6 months of maintenance phase therapy without a prior dose increase during that phase.

Estimated Enrollment: 90
Study Start Date: August 2014
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: COR-003
Male or female, ≥18 year of age, or of a minimal age as required by the local regulations with confirmed diagnosis of CS as defined according to the criteria in the guidelines for diagnosis of CS (Nieman 2008).
Drug: COR-003

Detailed Description:

This will be a single period, open-label, dose titration study to assess efficacy, safety, tolerability, and PK of COR-003 in subjects with CS. The trial design will identify both the minimally effective and maximally tolerated doses in this CS population. Following an initial screening period, this study will be conducted in 2 treatment phases as follows:

  • Dose titration phase: approximately 2 to 16 weeks to achieve an effective and tolerable maximum dose (the therapeutic dose)
  • Maintenance phase: 6 months of treatment at the therapeutic dose without a prior dose increase following the establishment of the appropriate dose identified in the titration phase;
  • Extended evaluation phase: 6 months of continued treatment after the maintenance phase (6 - 12 months); dose adjustments will be allowed as required for treatment

Efficacy will be assessed by measuring UFC concentrations at specified times as described in the clinical protocol.

Blood samples for the PK determination will be collected at the times indicated in the clinical protocol.

An independent Data Safety Monitoring Board (DSMB) will review the safety of the drug throughout the study. The constituents of the DSMB membership and a adjudication committee is specifically described in the clinical protocol.

Subjects completing the 6-month maintenance phase of the study will remain in the study for an additional 6 months for extended evaluations.

COR-003 will be provided under a compassionate use protocol for subjects who wish to continue treatment with COR-003.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

Subjects eligible for enrollment in the study must meet all the following criteria:

  1. Male or female, ≥18 year of age
  2. 2. Confirmed diagnosis of persistent or recurrent CS (with or without therapy) or newly diagnosed disease, if they are not candidates for surgery. CS will be defined according to the criteria in the guidelines for diagnosis of CS (Nieman 2008). Previous medical records will be collected and used to support the diagnosis. The diagnostic criteria for appropriateness of inclusion of each subject into the study will be reviewed by the Medical Monitor.• • Subjects MUST have elevated 24-hour UFC levels ≥1.5X ULN of assay based on a minimum of 4 measurements from adequately collected urine. Urine may be collected on sequential days.

    • Diagnosis of the disease will also need to be based on the association of clinical features of endogenous CS (see Appendix G), review of past medication history, excluding exogenous sources of glucocorticoids, and abnormal values from one of the following tests: i. Abnormal DST: Elevated 8 AM serum cortisol ≥1.8 ug/dL (50 nmol/L) after 1 mg dexamethasone orally at 11 PM the evening prior (if not conducted already in the diagnostic workup of the subject within the previous 2 months; previous test results and details of conduct will need to be available) ii. Elevated late night salivary cortisol concentrations (at least 2 measurements) >ULN at screening NOTE: For subjects with estimated glomerular filtration rate (eGFR as determined by Modified Diet in Renal Disease MDRD equation) >40 and <60 mL/min/1.73 m2 in addition to meeting the UFC criteria, late night salivary cortisol test results (≥2 measurements) MUST also demonstrate evidence of CS.

  3. Previously irradiated subjects will be allowed as long as the radiation treatment occurred > 4 years ago and they have not exhibited evidence for improvement in their underlying Cushing's disease for 6 months. The total number of previously irradiated subjects enrolled in this study will not exceed 10.

    • In the vast majority of subjects treated with radiation, efficacy is observed in <4 years.

  4. 4. Subjects who refuse surgery or in whom surgery will be delayed beyond the projected duration of this study will be permitted to participate.
  5. Confirmed diagnosis of persistent or recurrent endogenous hypercortisolemia as defined by elevated 24-hour UFC levels on repeated determinations (described in Inclusion #2) caused by either ACTH-dependent or ACTH-independent etiologies.

    • Cushing's Disease (CD) which is specifically defined as mean 24-hour UFC level of ≥1.5X ULN on repeated determination, morning plasma corticotropin (ACTH) level of 5 ng/L (1.1 nmol /L) or more, a confirmed pituitary source of CD (documentation of ACTH immunoreactivity on pathological evaluation), and as determined by medical records (including surgical reports and pituitary imaging scans), or bilateral inferior petrosal sinus sampling (BIPSS) with a central to peripheral ratio of >2 before or >3 after corticotropin-releasing hormone (CRH) administration)
    • Ectopic ACTH secretion, not of pituitary origin
    • Ectopic CRH secretion
    • Adrenal-dependent CS (adrenal adenoma, adrenal autonomy)
    • Etiology unknown
  6. Subjects whose CS is due to Cushing's disease with or without radiographically visible adenomas may be enrolled based on a pituitary magnetic resonance imaging (MRI) scan may be enrolled as long as biochemical criteria in Inclusion Criteria #5 are met.
  7. Subjects on treatment for CS for whom treatment has been inadequate or not well tolerated must agree to the following minimum washout periods as determined by the nature of their treatment before baseline assessments are performed for participation in this study:

    • Inhibitors of steroidogenesis (including ketoconazole): 2 weeks
    • Dopamine agonists: bromocriptine (2 weeks), cabergoline (8 weeks)
    • Octreotide acetate LAR and lanreotide Autogel®: 12 weeks
    • Lanreotide SR/long-acting pasireotide: 8 weeks
    • Octreotide acetate (immediate release formulation) or short-acting pasireotide: 1 week
    • Mifepristone (RU 486): 4 weeks
  8. Subjects on megesterol acetate (medroxyprogesterone acetate) must agree to a wash out of ≥6 weeks prior to receiving the first dose of the study medication
  9. Subjects with impaired fasting glucose, diabetes and/or hypertension may be enrolled
  10. A female is eligible to enter and participate in the study if she is of:

    Non-child bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post-menopausal females are defined as being amenorrhoeic for greater than 1 year with an appropriate clinical profile, e.g. age appropriate, > 45 years, in the absence of hormone replacement therapy. However in questionable cases, a blood sample with FSH > 40MIU/ml and estradiol < 40pg/ml (<140 pmol/L) is confirmatory.


    Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the following acceptable contraceptive methods used consistently and correctly (i.e. in accordance with the approved product label and the instructions of the physician for the duration of the study - screening to follow-up contact):

    • Complete abstinence from intercourse; or
    • Male partner is sterile prior to female subject entry into the study, and this male partner is the sole partner for that subject; or
    • Implants of levonorgestral inserted for at least 1 month prior to the study medication administration but not beyond the third successive year following insertion; or
    • Oral contraceptive (combined or progestogen only) administered for at least one monthly cycle prior to study medication administration; or
    • Double barrier method: condom or occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository); or
    • An intrauterine device (IUD); or
    • Estrogenic vaginal ring; or
    • Percutaneous contraceptive patches
  11. 12-lead ECGs show no acute ischemia or clinically significant abnormality needing medical intervention.
  12. Ability to comprehend and comply with procedures.
  13. Agree to commit to participate in the current protocol.
  14. Subjects provide written informed consent prior to any study procedures being performed (all subjects should be able to understand the informed consent form and any other documents that subjects are required to read).

Exclusion Criteria:

Subjects will be excluded from the study if any of the following criteria are met:

  1. De novo Cushing´s disease AND a candidate for pituitary surgery

    • If surgery is to be delayed for >6 months, subjects may be allowed to participate in the trial while awaiting surgery, but must agree to complete this study prior to surgery.

  2. Subjects treated with radiation within the previous 4 years or >4 years and with evidence of improvement in their disease within 6 months prior to Screening.

    • In the majority of subjects treated with radiation, efficacy is observed in <4 years.

  3. Subjects who have been treated with mitotane within 6 months of screening or have levels exceeding 5 μg/mL.
  4. Pseudo-Cushing's syndrome based on clinical assessment of the investigator. Appendix H describes a number of conditions in which elevated cortisol levels may be observed in the absence of Cushing's syndrome, sometimes referred to as Pseudo-Cushing's syndrome
  5. Subjects with adrenal carcinoma.
  6. Body habits preventing repeated venipuncture as required by protocol.
  7. Subject is currently in another study or has received any investigational treatment (drug, biological agent or device) within 30 days or 5 half-lives of screening, whichever is longer.
  8. Male and female subjects with QTc interval of >470 msec.
  9. 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 <3.0 meq/L.
  10. Subjects with a non-endogenous source of hypercortisolemia such as exogenous source of glucocorticoids or therapeutic use of ACTH.
  11. History of malignancy, other than thyroid, early stage prostate, squamous cell and basal cell carcinoma, within 3 years prior to Screening. Subjects with history of carcinoma must have a life expectancy of >1 year and must be on stable doses of their specific therapies. Subjects with early stage prostate cancer undergoing no treatment due to low grade potential may be enrolled.
  12. Diagnosis of HIV.
  13. History of persistent uncontrolled hypertension (>180/120 mmHg) despite medical intervention.
  14. Subjects with hypercholesterolemia who are on current atorvastatin or simvastatin and not willing or unable to change to alternative therapies as noted (pravastatin, fluvastatin, and rosuvastatin) within 2 weeks of study screening. Subjects may sign informed consent and then immediately begin screening assessments once they have discontinued the prohibited statin.
  15. Subjects requiring repeated frequent hospitalizations for management of hyperglycemic episodes.
  16. Subjects with decreased renal function as defined by eGFR <40 mL/min/1.73 m2, using MDRD equation for estimating renal function (eGFR).
  17. Any other clinically significant medical condition, as determined by the Investigator that precludes enrollment and participation in the study through completion (for example, New York Heart Association (NYHA) class III or IV congestive heart failure).
  18. Known hepatic disease, other than mild to moderate hepatic steatosis consistent with fatty infiltration (non-alcoholic steatohepatitis [NASH]).
  19. History of recurrent gall stone attacks or pancreatitis.
  20. Positive for hepatitis B surface antigen (HbsAg) or positive hepatitis C test.
  21. Liver function tests (LFT) must not be above the following cut-offs at screening: ALT and/or AST >3.0X ULN, GGT >2X ULN, and total bilirubin >2X ULN. If all LFTs are within normal limits (WNL) and total bilirubin is elevated, examination of direct and indirect bilirubin may be conducted. Subjects with indirect total bilirubin up to 3X ULN are presumed to have Gilbert's syndrome and may be enrolled if all other LFTs are WNL.
  22. History of documented clinically significant liver function abnormalities requiring drug discontinuation on ketoconazole or closely related chemical analogues (for example, itraconazole).
  23. Presence of any other clinically significant medical condition, as determined by the Investigator that would preclude the subject from being able to follow instructions or to perform the necessary procedures (for example, psychiatric instability or severe disability).
  24. Compression of the optic chiasm.
  25. Abnormal free T4. Subjects with TSH <LLN and normal free T4 are permitted to participate in the study.
  26. Subjects who have a history of alcohol or drug abuse in the 6 month period prior to enrollment.
  27. The subject is currently taking any H2 receptor antagonists, proton-pump inhibitors, or sucralfate (which inhibit absorption of COR-003). A list of orally acceptable antacids (for example, Mylanta and Maalox) will be provided, and can only be taken a minimum of 2 hours after dosing of COR-003.
  28. The subject is receiving the following concomitant therapies:

    • Weight loss medications (prescription or over the counter)
    • Acetaminophen >3 g total daily dose (due to increased hepatotoxicity)
    • Co-administration of strong inducers or inhibitors of CYP3A4 enzyme system that may interfere with COR-003 and cannot be discontinued prior to dosing (see Section 10.2 and Appendix K for further details)
    • Statins other than pravastatin, fluvastatin and rosuvastatin
    • The following herbal medicines are prohibited: St John's Wort, echinacea, gingko, goldenseal, yohimbe, red rice yeast, danshen, silybum marianum, Asian ginseng, schissandra sphenanther, shankhapushi, and Asian herb mixture (Xiao chai hu tang and Salboku-to).
    • Topical or inhaled steroids.
    • Carbamazepine, fenofibrate, carbenoxolone.
    • Excessive ingestion of genuine licorice.
  29. Pregnant women or lactating women, or women of child bearing potential not practicing a medically acceptable method for birth control or sexually active men not using contraception. Women must agree to continue to use an acceptable method of contraception and men must use condoms, if sexually active. All forms of contraception, used by male and female subjects, must be used during the course of the study and for 2 weeks after the study is completed.
  30. Any other condition which would jeopardize the risk of subject participation in the trial in the opinion of the Investigator
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01838551

Contact: Nick France, MD 215-380-8825

  Show 36 Study Locations
Sponsors and Collaborators
Cortendo AB
Study Director: Nick France, MD Cortendo AB
  More Information

No publications provided

Responsible Party: Cortendo AB Identifier: NCT01838551     History of Changes
Other Study ID Numbers: COR-003
Study First Received: April 19, 2013
Last Updated: June 25, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Cushing Syndrome
Adrenal Gland Diseases
Adrenocortical Hyperfunction
Endocrine System Diseases
Pathologic Processes processed this record on July 27, 2015