A Study to Assess the Safety and Efficacy of Levoketoconazole in the Treatment of Endogenous Cushing's Syndrome.
Condition: Endogenous Cushing's Syndrome
MeSH terms: Cushing Syndrome; Syndrome
Intervention: Levoketoconazole; Placebo
Intervention description: During the double-blind Withdrawal Phase, patients will receive up to 1200 mg levoketoconazole daily.
During the double-blind Restoration Phase, patients will receive levoketoconazole plus placebo.; During the double-blind Withdrawal Phase, patients will receive placebo tablets.
During the double-blind Restoration Phase, patients will receive placebo plus levoketoconazole.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 84.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Cushing Syndrome, Adrenocortical Hyperfunction

Summary:

      This is a double-blind, randomized, placebo-controlled withdrawal and rescue/restoration
      study in subjects with endogenous Cushing's Syndrome (CS) previously treated with single-arm,
      open-label levoketoconazole that will assess efficacy, safety, tolerability, and
      pharmacokinetics of levoketoconazole.
    

Eligibility criteria:

        INCLUSION CRITERIA:

        SONICS STUDY COMPLETERS:

        Completed the final SONICS visit (M12) and have demonstrated maintenance of clinical
        response on a stable Therapeutic Dose of levoketoconazole for at least 12 weeks prior to
        study entry.

        ALL OTHERS:

          -  Confirmed newly diagnosed, persistent or recurrent endogenous Cushing's syndrome of
             any etiology, except secondary to malignancy (including pituitary or adrenal
             carcinoma).

          -  Elevated mean 24-hour Urinary Free Cortisol (UFC) levels at least 1.5X upper limit of
             the normative range of the study's central laboratory assay and from a minimum of
             three measurements from adequately collected urine.

          -  Presence of abnormal values from at least one of these two diagnostic tests:

               -  Abnormal Dexamethasone Suppression Test (DST) OR

               -  Elevated late night salivary cortisol concentrations (at least two measurements)
                  each greater than the upper limit of the study's central laboratory normative
                  range

          -  Non-candidates for CS-specific surgery, refuse surgery or surgery will be delayed
             until after study completion and agree to complete this study prior to surgery.

          -  If post-surgical for CS-specific surgery, then no significant post-operative sequelae
             remain and the risk of such sequelae is considered negligible.

        EXCLUSION CRITERIA:

        Subjects will be excluded from the study if ANY of the following criteria are met (NOTE:
        exclusion criteria apply to and must be assessed in both cohorts):

          -  Enrolled in SONICS but have not completed SONICS through Visit M12.

          -  Pseudo-Cushing's syndrome based on assessment of the Investigator.

          -  Cyclic Cushing's syndrome with multi-week periods of apparent spontaneous CS
             remission.

          -  Non-endogenous source of hypercortisolism, including pharmacological corticosteroids
             or ACTH.

          -  Radiotherapy of any modality directed against the source of hypercortisolism within
             the last 5 years.

          -  Treatment with mitotane within 6 months of enrollment.

          -  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).

          -  Clinical or radiological signs of compression of the optic chiasm.