Treatment for Endogenous Cushing's Syndrome (SONICS)

Cortendo

Status and phase: Completed; Phase 3

Conditions: Endogenous Cushing's Syndrome

Treatments: Drug: Levoketoconazole

Study type: Interventional

Funder types: Industry

Identifiers

NCT01838551

COR-2012-01

Details and patient eligibility

About

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.

Full description

This is an open label, single arm study with a Screening Phase, a Dose Titration Phase, a 6-month Maintenance Phase, and a 6-month Extended Evaluation Phase designed to assess efficacy, safety, tolerability, and PK of COR-003 in subjects with endogenous CS.

Following an initial screening and washout period, as applicable, this study will be conducted in three treatment phases as follows:

• Dose Titration Phase: approximately 2 to 21 weeks to achieve an effective and tolerable maximum dose (the Therapeutic Dose). Dose titration will occur in increments of 150 mg with a starting dose of 150 mg twice daily (BID) over a period of approximately 2 to 21 weeks to achieve an effective and tolerable maximum dose (the Therapeutic Dose).
• Maintenance Phase: 6 months of treatment at the Therapeutic Dose following the Dose Titration Phase. Once the Therapeutic Dose has been reached and confirmed from the mean of a total of four adequately collected 24 hour urine collections for UFC measurements, subjects will enter into the Maintenance Phase of the study and will be asked to return to the clinic monthly for 6 months for assessment of efficacy and safety. During the Maintenance Phase, doses may not be increased to maintain UFC levels at or below ULN of the assay unless it is confirmed that a dose increase is deemed medically necessary at the discretion of the Investigator after discussion with the Medical Monitor. Prior to the End of Maintenance Phase Visit, four complete 24 hour urine collections will be obtained and subjects may enter the Extended Evaluation Phase.
• Extended Evaluation Phase: 6 months of continued treatment after the Maintenance Phase. In the 6-month Extended Evaluation Phase, subjects will return to the clinical site every 90 days (±14 days) for safety and efficacy evaluations.

Efficacy will be assessed primarily by measuring mean UFC concentrations at specified times as described in the clinical protocol. Safety will be assessed primarily by physical examinations with vital sign measurements, adverse events, clinical laboratory measures, electrocardiography, and pituitary MRI.

An independent Data Safety Monitoring Board (DSMB) will review the safety of the drug throughout the study. Membership of the DSMB is described in a Charter.

Enrollment: 94 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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94 participants in 8 patient groups

Levoketoconazole DL0

Experimental group

Description:

Levoketoconazole Tablets Dose Level 0 Once Daily

Treatment:

Drug: Levoketoconazole

Levoketoconazole DL1

Experimental group

Description:

Levoketoconazole Tablets Dose Level 1 Twice Daily

Treatment:

Drug: Levoketoconazole

Levoketoconazole DL2

Experimental group

Description:

Levoketoconazole Tablets Dose Level 1 Twice Daily

Treatment:

Drug: Levoketoconazole

Levoketoconazole DL3

Experimental group

Description:

Levoketoconazole Tablets Dose Level 3 Twice Daily

Treatment:

Drug: Levoketoconazole

Levoketoconazole DL4

Experimental group

Description:

Levoketoconazole Tablets Dose Level 4 Twice Daily

Treatment:

Drug: Levoketoconazole

Levoketoconazole DL5

Experimental group

Description:

Levoketoconazole Tablets Dose Level 5 Twice Daily

Treatment:

Drug: Levoketoconazole

Levoketoconazole DL6

Experimental group

Description:

Levoketoconazole Tablets Dose Level 6 Twice Daily

Treatment:

Drug: Levoketoconazole

Levoketoconazole DL7

Experimental group

Description:

Levoketoconazole Tablets Dose Level 7 Twice Daily

Treatment:

Drug: Levoketoconazole