Treatment for Endogenous Cushing's Syndrome

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2015 by Cortendo AB
Sponsor:
Information provided by (Responsible Party):
Cortendo AB
ClinicalTrials.gov Identifier:
NCT01838551
First received: April 19, 2013
Last updated: August 14, 2015
Last verified: August 2015
  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 (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.

  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 years of age
  2. 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.
  3. Confirmed diagnosis of newly diagnosed, persistent or recurrent CD if subjects are not candidates for surgery or radiotherapy CD is defined according to the criteria in the Endocrine Society Clinical Practice Guideline for diagnosis of CD (Nieman 2008). Previous medical records will be collected and used to support the diagnosis of CD.

    Specifically, CD is 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
    • Either MRI confirmation of pituitary macroadenoma, or inferior petrosal sinus gradient >3 after corticotropin-releasing hormone (CRH) stimulation for those patients with a microadenoma, or for subjects who have had prior pituitary surgery, histopathology confirming and ACTH-staining adenoma. If inferior petrosal sampling had been performed without CRH, then a central to peripheral pre-stimulation gradient >2 is required
  4. Confirmed diagnosis of newly diagnosed, persistent or recurrent endogenous CS of other etiology if subjects are not candidates for surgery or radiotherapy. CS will be defined according to the criteria in the Endocrine Society Clinical Practice Guideline for diagnosis of CS (Nieman 2008). Previous medical records will be collected and used to support the diagnosis, and the differentiation of the cause of CS, specifically

    • Mean 24-hour UFC level of ≥1.5X ULN on repeated determination
    • Ectopic ACTH secretion, not of pituitary origin
    • Ectopic CRH secretion
    • Adrenal-dependent CS (adrenal adenoma, adrenal autonomy)
    • Etiology unknown
  5. Subjects MUST have elevated mean 24-hour UFC levels ≥1.5X ULN of assay based on a minimum of four measurements from adequately collected urine. Urine may be collected on sequential days.
  6. In addition to elevated mean UFC, presence of abnormal values from one of the following tests:

    • 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 before start of Screening Phase; in that case previous test results and details of conduct will need to be available by the Baseline visit)
    • Elevated late night salivary cortisol concentrations (at least two measurements) >ULN 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.
  7. Previously irradiated subjects with CD or CS of other etiology will be allowed as long as the radiation treatment occurred > 4 years ago and subjects 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.
  8. Subjects with CD or CS of other etiology who are not candidates for surgery, refuse surgery, or in whom surgery will 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. For subjects who have already undergone surgery, a minimum of 3 months should have elapsed before the subject can be deemed a surgical failure.
  9. Subjects on treatment for CD or endogenous CS of other etiology for whom treatment has been inadequate or not well tolerated must agree to the following minimum washout periods prior to the Baseline Visit:

    • 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
  10. Subjects on megesterol acetate (medroxyprogesterone acetate) must agree to a washout period of at least 6 weeks prior to the Baseline Visit
  11. 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 > 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.

    OR Child bearing potential and agrees to use highly effective methods of birth control while participating in the study and for 2 weeks after the study is completed.

  12. Fertile men must also agree to use a medically acceptable form of birth control while on study drug and up to 2 weeks after the study is completed.
  13. Able to comprehend and comply with procedures.

Exclusion Criteria

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

  1. Subjects with Pseudo-Cushing's syndrome based on assessment of the investigator.
  2. Subjects with cyclic Cushing's syndrome based on assessment of the investigator
  3. Subjects with a non-endogenous source of hypercortisolism such as exogenous source of glucocorticoids or therapeutic use of ACTH.
  4. Known inherited syndrome as the cause of hypercortisolism, including but not limited to multiple endocrine neoplasia Type 1, McCune Albright Syndrome and Carney Complex
  5. Subjects with adrenal carcinoma
  6. History of malignancy, other than thyroid, early stage prostate, squamous cell and basal cell carcinoma, within 3 years prior to the Screening Phase. Subjects with history of such allowed 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.
  7. Clinical or radiological signs of compression of the optic chiasm.
  8. Major surgery within 1 month prior to enrollment (ICF signing)
  9. Subjects with clinically significant abnormality in 12-lead ECGs during the Screening Phase needing medical intervention.
  10. Subjects with QTc interval of >470 msec during the Screening Phase.
  11. Subjects with a 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.
  12. Preexisting hepatic disease; subjects with mild to moderate hepatic steatosis consistent with fatty infiltration (non-alcoholic fatty liver disease [NAFLD] are allowed).
  13. Positive for hepatitis B surface antigen (HbsAg) or positive hepatitis C test.
  14. History or symptoms of recurrent symptomatic cholelithiasis or pancreatitis.
  15. Liver function tests (LFT) must not be above the following cut-offs during the Screening Phase:

    • ALT and/or AST >3 X ULN
    • Total bilirubin >2 X ULN If all LFTs are within normal limits (WNL) and total bilirubin (TBN) is elevated, examination of direct and indirect bilirubin may be conducted. Subjects with isolated indirect TBN up to 3X ULN are presumed to have Gilbert's syndrome and may be enrolled if all other LFTs are within normal levels.
  16. History of documented or suspected drug-induced liver injury requiring drug discontinuation of ketoconazole or any azole antifungals.
  17. Pregnant or lactating women
  18. HIV-positive.
  19. History of persistent uncontrolled hypertension (>180/120 mmHg) despite medical intervention.
  20. Subjects with hypercholesterolemia who are currently treated with atorvastatin, lovastatin or simvastatin and not willing or unable to change to alternative therapies with pravastatin, fluvastatin, and rosuvastatin within 2 weeks of start of the Screening Phase.
  21. Body habitus preventing repeated venipuncture as required by protocol.
  22. 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 treatment, whichever is longer.
  23. Repeated hospitalization for hyperglycemia or any complication of hyperglycemia and diabetes during the last 12 months
  24. Subjects with decreased renal function as defined by eGFR <40 mL/min/1.73 m2, using MDRD equation for estimating renal function (eGFR).
  25. 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 to perform the necessary procedures (for example, psychiatric instability or severe disability).
  26. Abnormal free T4. Subjects with TSH <LLN and normal free T4 are permitted to participate in the study.
  27. Subjects who have a history of alcohol or drug abuse in the 6 month period prior to enrollment.
  28. Subjects who have been treated with mitotane within 6 months of the Screening Phase.
  29. Subjects who are currently taking any H2 receptor antagonists, proton-pump inhibitors, or sucralfate (all of 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.
  30. Subjects who receive any prohibited concomitant medication:

    • 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 the metabolism of COR-003 and cannot be discontinued prior to first dose
    • 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
    • Carbamazipine, fenofibrate, carbenoxolone.
    • Ingestion of genuine licorice.
  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: Nick France, MD 215-380-8825 nfrance@cortendo.com

  Show 42 Study Locations
Sponsors and Collaborators
Cortendo AB
Investigators
Study Director: Nick France, MD 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, 2015
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on September 02, 2015