Treatment for Endogenous Cushing's Syndrome

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Cortendo AB
Sponsor:
Information provided by (Responsible Party):
Cortendo AB
ClinicalTrials.gov Identifier:
NCT01838551
First received: April 19, 2013
Last updated: August 14, 2014
Last verified: August 2014
  Purpose

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 (2S, 4R-ketoconazole) 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.

  Eligibility

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

Inclusion Criteria:

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

  1. Male or female, ≥18 year of age
  2. Confirmed diagnosis of persistent or recurrent CS (with or without therapy) or newly diagnosed disease, if they are not candidates for surgery. Subjects in whom surgery will be delayed beyond 5 months will be permitted to participate. 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. Diagnosis of the disease will be based on the association of clinical features of endogenous CS (see Appendix G in clinical protocol), review of past medication history, excluding exogenous sources of glucocorticoids, and abnormal values from two of the three following tests:

    • 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.
    • 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 6 months; previous test results and details of conduct will need to be available; normal serum cortisol ≤ 1.4 ug/dL)
    • 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 MDRD equation >40 and <60 mL/min) a late night salivary cortisol test (≥2 measurements) MUST be conducted in addition to measuring UFC levels to demonstrate evidence of CS.]
  3. Previously irradiated subjects will be allowed as long as the radiation treatment occurred ≥2 years ago and they do have stable UFC levels based on 24-hour urine collections for at least 6 months. The total number of previously irradiated subjects will not exceed 10.

    • In the vast majority of subjects treated with radiation, efficacy is observed in <2 years.

  4. Confirmed diagnosis of persistent or recurrent endogenous hypercortisolemia as defined by UFC concentrations on repeated determinations (described in Inclusion #2) caused by either ACTH-dependent or ACTH-independent etiologies.
  5. 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: 2weeks; subjects on ketoconazole will be considered inadequately treated if they had failed to normalize UFC with a dose lower than or equal to 600 mg/day (also see Exclusion 7 below).
    • Dopamine agonists: bromocriptine (2 week), 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
  6. Subjects on megasterol acetate (medroxyprogesterone acetate) must agree to a wash out of ≥6 weeks prior to receiving the first dose of the study medication.
  7. Female subjects should be either post-menopausal, surgically sterile, or women of child-bearing potential (WOCP) with a negative serum beta human chorionic gonadotropin (βhCG) pregnancy test prior to entering the study and who agree to use an acceptable method of contraception, for the duration of the study. Condoms will be considered an acceptable form of contraceptive.
  8. 12-lead ECGs show no acute ischemia or clinically significant abnormality needing medical intervention
  9. Ability to comprehend and comply with procedures
  10. Agree to commit to participate in the current protocol
  11. 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 >5 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 2 years.

    • In the vast majority of subjects treated with radiation, efficacy is observed in <2 years.

  3. Characteristics of pseudo-CS (see Appendix H in clinical protocol)
  4. Subjects with adrenal carcinoma
  5. Body Mass Index (BMI) exceeding 50 kg/m2
  6. Body habitus 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. History of significant abnormalities in liver function tests on ketoconazole; history of therapeutic response failure to ketoconazole as defined by lack of normalization of UFC at a dose greater than 800 mg/day; lack of therapeutic response failure at maximum dose of mitotane
  9. Male and female subjects with QTc interval of >470 msec
  10. History of Torsades des Pointes or ventricular tachycardia or ventricular fibrillation
  11. Subjects with a non-endogenous source of hypercortisolemia such as exogenous source of glucocorticoids or therapeutic use of ACTH
  12. History of malignancy, other than thyroid, early stage prostate, squamous cell and basal cell carcinoma, within 3 years prior to the initial dose of the study medication. 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.
  13. Diagnosis of HIV
  14. History of persistent uncontrolled hypertension (>210/110 mmHg) despite medical intervention
  15. Subjects with hypercholesterolemia who are on current atorvastatin or simvistatin and not willing or unable to change to alternative therapies as noted (pravastatin, fluvastatin, and rosuvastatin) with 2 weeks of study screening
  16. Subjects with T2DM or with a history of hyperglycemic episodes requiring repeated, frequent hospitalizations
  17. Subjects with decreased renal function as defined by eGFR ≤40 mL/min, using Modified Diet in Renal Disease (MDRD) equation for estimating renal function (eGFR).
  18. 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).
  19. Known hepatic disease, other than mild to moderate hepatic steatosis consistent with fatty infiltration (non-alcoholic steatohepatitis [NASH]), with ongoing sustained biochemical activity (subjects with CS would be at risk for NASH)
  20. History of recurrent gall stone attacks or pancreatitis
  21. Positive for hepatitis B surface antigen (HbsAg) or positive hepatitis C test
  22. Liver function tests (LFT) must not be above the following cut-offs at screening: ALT and/or AST >3.0X ULN, alkaline phosphatase (AP) >1.5X ULN and total bilirubin >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.
  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. Excessive alcohol intake (>20 g per day for females (1.5 standard alcohol drinks) or >30 g per day for males (2.0 standard alcohol drinks) (a standard drink contains 14 g of alcohol: 12 oz of beer, 5 oz of wine or 1.5 oz of spirits) or drug abuse. (1.0 fluid oz (US) = 29.57 ml)
  27. The subject is currently taking any H2 receptor antagonists or proton-pump inhibitors (which inhibit absorption of COR-003). Only over-the- counter liquid and tablet antacids are allowed which should be used in moderation and 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)
    • Coadministration of COR-003 and drugs primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentrations of the drugs that could increase or prolong both therapeutic and/or adverse effects. Therefore, appropriate dosage adjustments may be necessary.

      • Medications with metabolism largely mediated by CYP3A4 and a narrow therapeutic margin include: cyclosporine, midazolam, triazolam, alprazolam, digoxin, coumarin-derivatives, phenytoin, rifampin, erythromycin, clarithromycin, loratadine, astemizole, terfenadine, nicotinic acids, resins, orlistat, sibutramine, HIV protease inhibitors, thiazolidinodiones, aliskiren, and spironolactone.
      • A complete list of medications metabolized by or with an effect on cytochrome P450 3A4 is provided in Appendix K. Also see Section 10.2.
    • Coadministration of strong inducers or inhibitors of CYP3A4 enzyme system that may interfere with COR-003 and cannot be discontinued prior to the start of the study (see Appendix K for the list)
    • Statins other than pravastatin, fluvastatin and rosuvastatin
    • Following herbal medicines should be avoided: St John's Wort, yohimbe and red rice yeast
    • Potent topical steroids, containing urea or salicylic acid, which are applied over 20% of the body
    • Inhaled steroid medications that exceed minimal to moderate use
    • Carbamazipine, fenofibrate, carbenoxolone
    • Excessive ingestion of genuine licorice
  29. Pregnant or lactating women
  30. Any other condition which would increase the risk of 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 ClinicalTrials.gov identifier: NCT01838551

Contacts
Contact: Theodore R Koziol, Ph.D. 610-254-9225 trkoziol@cortendo.com

Locations
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21287
Contact: Thomas Mitchell    410-614-5678    tnm@jhmi.edug   
Principal Investigator: Roberto Salvatori, MD         
United States, New York
Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
Contact: Melissa Diamond    212-241-5389    melissa.diamond@mssm.edu   
Principal Investigator: Eliza Geer         
United States, Ohio
Cleveland Clinic Recruiting
Cleveland, Ohio, United States, 44195
Contact: Amy Orasko    216-444-3267    oraskoA@ccf.org   
Principal Investigator: Ned Kennedy, MD         
Ohio State University Wexner Medical Center Recruiting
Columbus, Ohio, United States, 43203
Contact: Christy Sykes    614-688-5901    Christiane.Sykes@osumc.edu   
Principal Investigator: Lawrence Kirschner         
United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104-5160
Contact: Helen Peachey    215-898-5664    peacheyh@mail.med.upenn.edu   
Principal Investigator: Peter Snyder, MD         
Belgium
University Hospitals Leuven Department of Endocrinology Recruiting
Leuven, Belgium, 3000
Contact: Hilde Morobé    +3216348554    hilde.morobe@uzleuven.be   
Principal Investigator: Marie Bex, MD         
Netherlands
Erasmus MC, Dpt. Of Internal Medicine, Division of Endocrinology Recruiting
Rotterdam, Netherlands, 3015 CE
Contact: Sjaan Poldermans    0031-10 703 15 98    b.poldermans@erasmusmc.nl   
Principal Investigator: Richard Feelders, MD         
Sponsors and Collaborators
Cortendo AB
  More Information

No publications provided

Responsible Party: Cortendo AB
ClinicalTrials.gov Identifier: NCT01838551     History of Changes
Other Study ID Numbers: COR-003
Study First Received: April 19, 2013
Last Updated: August 14, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Syndrome
Cushing Syndrome
Disease
Pathologic Processes
Adrenocortical Hyperfunction
Adrenal Gland Diseases
Endocrine System Diseases

ClinicalTrials.gov processed this record on September 18, 2014