A Double-blind, Placebo-Controlled, Randomized Withdrawal Following Open-label Therapy Study to Assess the Safety and Efficacy of Levoketoconazole (2S,4R-ketoconazole) in the Treatment of Endogenous Cushing's Syndrome

The following categories of potential subjects, categorized by prior use of levoketoconazole, may be
eligible if the following 11 inclusion criteria are all met:
*Naïve to levoketoconazole;
*Completers of SONICS visit M12 who are not currently on levoketoconazole (i.e. not actively receiving open-label treatment after SONICS as part of an EAP or OLE study)
1. Male or female and at least 18 years of age.
2. Able and willing 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 newly diagnosed, persistent or recurrent endogenous Cushing*s syndrome of any etiology,
except secondary to malignancy (including pituitary or adrenal carcinoma). Persistence will not be
considered confirmed until 6 weeks or more post-surgery.
The following historical evidence will be considered as sufficient to establish the cause of endogenous
Cushing*s syndrome as being due to Cushing*s disease (i.e. ACTH-dependent of pituitary origin)
specifically:
*Pathological (e.g. adrenocorticotropic hormone [ACTH]-staining) or post-surgical confirmation
of the diagnosis of CD (i.e. documented adrenal insufficiency post-adenomectomy or posthypophysectomy)
OR
*Intermediate, normal or elevated plasma ACTH (i.e. at least 5 pg/mL [1.1 pmol/L]) PLUS
For tumors 6 mm and above by imaging:
a) Inferior petrosal sinus sampled (IPSS) ACTH central:plasma gradient at least 2 before
corticotropin-releasing hormone (CRH) or at least 3 after CRH, OR in the absence of
IPSS, either:
b) Positive ACTH and/or cortisol response to CRH or desmopressin or combined CRHdesmopressin
stimulation plus high-dose (8 mg) dexamethasone suppression of blood
cortisol, ideally on more than one occasion OR
c) Other adequate diagnostic testing. Such cases must be discussed with and explicitly
approved by the Medical Monitor, and the specific diagnostic criteria used to establish the
diagnosis of CD must be documented.
For tumors below 6 mm or not visible by Magnetic Resonance Imaging (MRI):
a) IPSS with ACTH central:plasma gradient at least 2 before CRH or at least 3 after
CRH.
b) Other adequate diagnostic testing. In the absence of IPSS, an individual might be
eligible if CD was otherwise confirmed via adequate testing. Such cases must be
discussed with and explicitly approved by the Medical Monitor, and the specific
diagnostic criteria used to establish the diagnosis of CD must be documented.
4. Elevated mean 24-hour UFC levels at least 1.5X ULN of the normative range of the study*s central laboratory assay and from a minimum of three measurements from adequately collected urine; the study*s central laboratory must be used for all qualifying measurements.
NOTE: This criterion does not apply to subjects currently on levoketoconazole.
5. Presence of abnormal values from at least one of these two diagnostic tests3 (discrepancies between test findings will not be investigated nor considered exclusionary):
*Abnormal Dexamethasone Suppression Test (DST): Elevated 8 AM blood cortisol at least
1.8 *g/dL (50 nmol/L) after 1 mg dexamethasone orally at 11 PM the evening prior with
concurrent dexamethasone blood concentration greater than 5.6 nmol/liter (220 ng/dL) (results
from within the 2 months prior to start of Screening or newly tested with results available by the
Baseline Visit [TM0]) OR
*Elevated LNSC concentrations (at least two measurements) each greater than the ULN of the
study*s central laboratory normative range; the study*s test kit and lab must be used for all
qualifying measurements.
NOTE: Abnormal LNSC is required among eligible subjects with estimated glomerular filtration rate
(eGFR as determined by Modified Diet in Renal Disease MDRD equation) above 40 and below 60
mL/min/1.73 m2 .
NOTE: This criterion does not apply to subjects currently on levoketoconazole.
6. 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.
7. If post-surgical for CS-specific surgery, then no significant post-operative sequelae remain and the
risk of such sequelae is considered negligible.
8. Agree to the following minimum washout periods prior to the Baseline Visit (TM0) (as applicable):
*Ketoconazole or metyrapone: 2 weeks;
*Dopamine agonists: bromocriptine (2 weeks), cabergoline (8 weeks);
*Octreotide acetate LAR, lanreotide Autogel® , pasireotide LAR: 12 weeks;
*Lanreotide SR: 8 weeks;
*Octreotide acetate (immediate release) or short-acting pasireotide: 1 week;
*Mifepristone (RU 486, KORLYM® ): 4 weeks;
*Megestrol acetate or medroxyprogesterone acetate (and selected other synthetic progestins):
6 weeks.
9. Females who are either of non-child bearing potential (i.e. incapable of becoming pregnant):
*Post-menopausal, defined as age 50 or older with amenorrhea for more than 1 year or any age with
serum follicle stimulating hormone (FSH) at least 23 mIU/mL and estradiol no more
than 40 pg/mL (140 pmol/L) OR
*Surgically sterile*documented hysterectomy and/or bilateral oophorectomy or tubal ligation.
OR
*Females of child-bearing potential who agree to use highly effective methods of birth control
while participating and for 2 weeks after participation has completed (abstinence is considered
acceptable if routinely practiced).
10. Men who, if fertile, agree to use an acceptable form of birth control, including abstinence if routinely
practiced, while enrolled and for 2 weeks after participation has completed.
11. Able to comprehend and comply with all procedures.
(protocol page 49 - 52)

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):
1. Enrolled or early terminated from SONICS or currently on levoketoconazole.
2. Pseudo-Cushing*s syndrome based on assessment of the Investigator.
3. Cyclic Cushing*s syndrome with multi-week periods of apparent spontaneous CS remission.
4. Non-endogenous source of hypercortisolism, including pharmacological corticosteroids or ACTH.
5. Radiotherapy of any modality directed against the source of hypercortisolism within the last 5 years.
6. Treatment with mitotane within 6 months of enrollment.
7. History of malignancy, including adrenal or pituitary carcinomas (other than low-risk, welldifferentiated
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).
8. Clinical or radiological signs of compression of the optic chiasm.
9. Major surgery within 1 month of Screening (or within 6 weeks for pituitary surgery).
10. Clinically significant abnormality in 12-lead electrocardiogram (ECG) during the Screening Phase
requiring medical intervention (may be eligible once stable, to be determined case by case).
11. QTc interval above 470 msec during the Screening Phase via central reader interpretation.
12. History of Torsades des Pointes, ventricular tachycardia, ventricular fibrillation, history of prolonged
QT syndrome (including first-degree family history).
13. Use of medications associated with possible, probable, or definite QT/QTc prolongation (unless
subsequently washed out).
14. Pre-existing hepatic disease (except for mild to moderate non-alcoholic fatty liver disease documented
by imaging or biopsy and with transaminase values within allowed limits).
15. Hepatitis B surface antigen (HbsAg) or hepatitis C-positive.
16. Human immunodeficiency virus (HIV)-positive.
17. History of symptomatic cholelithiasis with intact gallbladder.
18. History of pancreatitis.
19. Liver safety tests during the Screening Phase as follows:
*Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) above 3X ULN
*Alkaline phosphatase or Total bilirubin (TBN) above 2X ULN.
Subjects with isolated indirect TBN up to 3X ULN are presumed to have Gilbert*s syndrome and
may be enrolled if all other liver safety tests are within normal levels.
20. History of documented or suspected drug-induced liver injury to ketoconazole or any other azole drug.
21. Serum potassium below 4.0 mEq/L (unless subsequently corrected and stable).
22. Abnormal free thyroxine (FT4), unless subsequently corrected and stable for at least 4 weeks. Subjects
with thyroid-stimulating hormone (TSH) less than the lower limit of normal (LLN) and normal FT4
are potentially eligible without intervention.
23. History of persistent, uncontrolled hypertension despite medical intervention.
24. Hypercholesterolemia currently treated with atorvastatin, lovastatin or simvastatin and unwilling or
unable to change to alternative therapy with: pravastatin, fluvastatin, pitavastatin or rosuvastatin (must
switch statin at least 2 weeks prior to dosing) or another allowed therapy.
25. More than one hospitalization for hyperglycemia or complication of diabetes during the last 12 months
26. Decreased renal function as defined by eGFR below 40 mL/min/1.73 m2 , using MDRD equation for
eGFR.
27. Pregnant or lactating.
28. Body habitus preventing repeated venipuncture as required by protocol.
29. 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 perform necessary procedures (for
example, psychiatric instability or severe disability).
30. History of alcohol or drug abuse in the 6-month period prior to Screening.
31. Currently participating in another study or has received any investigational treatment (drug, biological
agent or device) other than levoketoconazole (COR-003), within prior 30 days or five half-lives of
treatment, whichever is longer.
32. Current use of any H2-receptor antagonists, proton-pump inhibitors, or sucralfate (all inhibit
absorption of levoketoconazole; subjects may be allowed to enroll after washout). A list of acceptable
oral antacids will be provided; if used, antacids must be ingested at least 2 hours after dosing of
levoketoconazole.
33. Current use of any prohibited concomitant medication that cannot be discontinued safely and washed
out completely prior to the Baseline Visit (TM0 or RW0, for the levoketoconazole-naïve and
SONICS-completers cohorts, respectively), including but not limited to the following (a more
complete list is included in Appendix J):
*Weight loss medications (prescription or over the counter);
*Acetaminophen (paracetamol) above 2 g total daily dose;
*Strong inducers or inhibitors of CYP3A4 enzyme system that may interfere with the metabolism
of levoketoconazole and cannot be discontinued prior to first dose;
*Herbal preparations: 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 corticosteroids;
*Carbamazepine, fenofibrate, carbenoxolone;
*Drugs that pose unacceptable risk due to overlapping or exaggerated toxicities or pharmacological
action due to presumed PK or PD interactions with levoketoconazole;
*Genuine licorice.
(protocol page 52 - 54)