Treatment for Endogenous Cushing's Syndrome
Condition: Endogenous Cushing's Syndrome
MeSH terms: Cushing Syndrome; Syndrome
Intervention: Levoketoconazole
Intervention description: Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Intervention model description: Dose titration
Masking: None (Open Label)
Masking description: A data integrity plan prevented the Sponsor from accessing summary efficacy data prior to locking the clinical database.
Enrollment: 94.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Cushing's disease; ectopic ACTH; adrenal Cushing's

Summary:

      The primary objectives of this study are to evaluate the clinical responder rate, defined as
      the proportion of subjects with normal UFC after 6 months of treatment with COR-003 in the
      Maintenance Phase without dose increase, and to evaluate the range of effective doses in
      subjects with various levels of hypercortisolism.
    

Eligibility criteria:

        Key Inclusion 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 Cushing's disease (CD)
             or endogenous CS of other etiology if subjects are not candidates for surgery or
             radiotherapy within the 18 months after enrollment.

             Previous medical records will be collected and used to support the diagnosis of CD or
             endogenous CS of other etiology, including the following etiologies:

               -  Ectopic adrenocorticotropic hormone (ACTH) secretion, i.e. ACTH not of pituitary
                  origin

               -  Ectopic corticotropin-releasing hormone (CRH) secretion

               -  Adrenal-dependent CS (i.e. adrenal adenoma (NOT carcinoma), adrenal hyperplasia,
                  etc.)

               -  Etiology unknown.

          4. Must have elevated mean 24 hour UFC levels ≥1.5X ULN based on the normative range of
             the central lab assay and on a minimum of four measurements from adequately collected
             urine.

          5. 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 micrograms/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

          6. Previously irradiated subjects with CD or endogenous 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 CD for 6 months prior to
             the Screening visit. The total number of previously irradiated subjects enrolled in
             this study will not exceed 10.

          7. Subjects with CD or CS of other etiology who are not candidates for surgery, refuse
             surgery, or in whom surgery will be delayed for at least 18 months following
             enrollment. Subjects may be allowed to participate in the trial while awaiting
             surgery, but must agree to complete this study prior to surgery.

          8. Subjects on treatment for CD or endogenous CS of other etiology for whom treatment has
             been inadequate or not well tolerated must agree to minimum washout periods prior to
             the Baseline Visit as specified.

        Key Exclusion Criteria

          1. Subjects with Pseudo-Cushing's syndrome based on assessment of the Investigator.

          2. Subjects with cyclic CS 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.

          7. Subjects with QTc interval of >470 msec during the Screening Phase.

          8. Pre-existing hepatic disease; subjects with mild to moderate hepatic steatosis
             consistent with fatty infiltration (non-alcoholic fatty liver disease [NAFLD] are
             allowed).

          9. History of documented or suspected drug-induced liver injury requiring drug
             discontinuation of ketoconazole or any azole antifungals.

         10. Subjects who receive any prohibited concomitant medication and cannot discontinue it
             safely prior to the Baseline Visit.