| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Endogenous Cushing's syndrome (CS) |
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| E.1.1.1 | Medical condition in easily understood language |
| In this condition patients produce an excessive level of a steroid hormone known as cortisol |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10011657 |
| E.1.2 | Term | Cushings syndrome |
| E.1.2 | System Organ Class | 100000004860 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To evaluate the efficacy of ascending doses of COR-003 (2S,4R-ketoconazole) in subjects with elevated levels of cortisol due to endogenous CS by assessment of reduction in UFC levels (based on adequately collected 24-hour urine collections)
• To identify the range of effective and safe doses of COR-003 that reduce mean UFC levels to ≤ the upper limit of the normal range (ULN) of the assay at month 6 of the maintenance phase of dosing without a prior dose increase in that phase |
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| E.2.2 | Secondary objectives of the trial |
• To identify the proportion of patients with either or both of the following:
o mean UFC ≤ULN or
o ≥50% reduction from baseline at month 6 of the maintenance phase
• To characterize the changes in serum and late night salivary cortisol concentrations over 6 months of dosing in the maintenance phase
• To assess the safety and tolerability of COR-003
• To evaluate the resultant changes in protocol-defined metabolic endpoints associated with reductions in UFC levels
• To assess the effects on clinical signs and symptoms of CS and the quality of life (QoL) measures obtained from the CushingQoL questionnaire
• To assess changes in diabetic and antihypertensive therapies following treatment with COR-003
• To evaluate the PK of COR-003 in subjects with CS
• To establish the dose (exposure) response relationship in reduction of UFC levels
• To describe the dose (exposure) response relationship for safety of COR-003, as data permit |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrollment in the study must meet all the following criteria:
1. Male or female ≥18 years of age
2. Confirmed diagnosis of persistent or recurrent CS (with or without therapy) or newly diagnosed disease, if they are not candidates for surgery. CS will be defined according to the criteria in the guidelines for diagnosis of CS (Nieman 2008).Previous medical records will be collected and used to support the diagnosis. The diagnostic criteria for appropriateness of inclusion of each subject into the study will be reviewed by the Medical Monitor.
3. Previously irradiated subjects will be allowed as long as the radiation treatment occurred > 4 years ago and they 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.
In the vast majority of subjects treated with radiation, efficacy is observed in
<4 years.
4. Subjects who refuse surgery or in whom surgery will be delayed beyond the projected duration of this study will be permitted to participate.
5. Confirmed diagnosis of persistent or recurrent endogenous hypercortisolemia as defined by elevated 24-hour UFC levels on repeated determinations (described in Inclusion #2) caused by either ACTH-dependent or ACTH-independent etiologies.
• Cushing’s Disease (CD) which is specifically 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, a confirmed
pituitary source of CD (documentation of ACTH immunoreactivity on
pathological evaluation), and as determined by medical records (including
surgical reports and pituitary imaging scans), or bilateral inferior petrosal
sinus sampling (BIPSS) with a central to peripheral ratio of >2 before or >3
after corticotropin-releasing hormone (CRH) administration)
• Ectopic ACTH secretion, not of pituitary origin
• Ectopic CRH secretion
• Adrenal-dependent CS (adrenal adenoma, adrenal autonomy)
• Etiology unknown
6. Subjects whose CS is due to Cushing’s disease without adenomas based on a pituitary magnetic resonance imaging (MRI) scan may be enrolled as long as biochemical criteria in Inclusion Criteria #5 are met.
7. Subjects on treatment for CS for whom treatment has been inadequate or not well tolerated must agree to the following minimum washout periods as determined by the nature of their treatment before baseline assessments are performed for participation
in this study:
• Inhibitors of steroidogenesis: 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
• Mitotane: >6 months and have serum concentrations <5 μg/mL
8. Subjects on megasterol acetate (medroxyprogesterone acetate) must agree to a wash out of ≥6 weeks prior to receiving the first dose of the study medication.
9. Subjects with impaired fasting glucose, diabetes and/or hypertension or any other manifestation of Cushing’s syndrome as long as they do not exceed exclusion criteria and subjects must meet biochemical inclusion criteria for the diagnosis of Cushing’s syndrome.
10. Female subjects should be either post-menopausal, surgically sterile, or women of child-bearing potential (WOCP) with a negative urine beta human chorionic gonadotropin (βhCG) pregnancy test prior to entering the study and who agree to use an acceptable method of contraception, for the duration of the study. Condoms will be considered an acceptable form of contraceptive.
11. 12-lead ECGs show no acute ischemia or clinically significant abnormality needing medical intervention
12. Ability to comprehend and comply with procedures
13. Agree to commit to participate in the current protocol
14. Subjects provide written informed consent prior to any study procedures being performed (all subjects should be able to understand the informed consent form and any other documents that subjects are required to read)
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| E.4 | Principal exclusion criteria |
Subjects will be excluded from the study if any of the following criteria are met:
1. De novo Cushing´s disease AND a candidate for pituitary surgery
• If surgery is to 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.
2. Subjects treated with radiation within the previous 4 years.
• In the vast majority of subjects treated with radiation, efficacy is observed in <4 years .
3. Subjects who have been treated with mitotane within 6 months of screening or have levels exceeding 5 μg/mL.
4. Pseudo-Cushing’s syndrome based on clinical assessment of the investigator.
5. Subjects with adrenal carcinoma
6. Body habitus preventing repeated venipuncture as required by protocol
7. 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 screening, whichever is longer
8. History of documented clinically significant liver function abnormalities requiring drug discontinuation on ketoconazole or closely related chemical analogues (for example, itraconazole).
9. Male and female subjects with QTc interval of >470 msec
10. 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
11. Subjects with a non-endogenous source of hypercortisolemia such as exogenous source of glucocorticoids or therapeutic use of ACTH
12. History of malignancy, other than thyroid, early stage prostate, squamous cell and basal cell carcinoma, within 3 years prior to the initial dose of the study medication. Subjects with history of 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.
13. Diagnosis of HIV
14. History of persistent uncontrolled hypertension (> 180/120 mmHg) despite medical intervention
15. Subjects with hypercholesterolemia who are on current atorvastatin or simvistatin and not willing or unable to change to alternative therapies as noted (pravastatin, fluvastatin, and rosuvastatin) with 2 weeks of study screening
16. Subjects with Type 2 Diabetes Mellitus (T2DM) or with a history of hyperglycemic episodes requiring repeated, frequent hospitalizations specifically for diabetic management
17. Subjects with decreased renal function as defined by eGFR ≤40 mL/min/1.73 m2, using Modified Diet in Renal Disease (MDRD) equation for estimating renal function (eGFR).
18. Any other clinically significant medical condition, as determined by the Investigator that precludes enrollment and participation in the study through completion (for example, New York Heart Association (NYHA) class III or IV congestive heart failure).
19. Known hepatic disease, other than mild to moderate hepatic steatosis consistent with fatty infiltration (non-alcoholic steatohepatitis [NASH]), with ongoing sustained biochemical activity (subjects with CS would be at risk for NASH)
20. History of recurrent gall stone attacks or pancreatitis
21. Positive for hepatitis B surface antigen (HbsAg) or positive hepatitis C test
22. Liver function tests (LFT) must not be above the following cut-offs at screening: ALT and/or AST >3.0X ULN, GGT >2X ULN, and total bilirubin >2X ULN. If all LFTs are within normal limits (WNL) and total bilirubin is elevated, examination of direct and indirect bilirubin may be conducted. Subjects with indirect total bilirubin up to 3X ULN are presumed to have Gilbert’s syndrome and may be enrolled if all other LFTs are WNL.
23. Presence of any other clinically significant medical condition, as determined by the Investigator that would preclude the subject from being able to follow instructions or to perform the necessary procedures (for example, psychiatric instability or severe disability)
24. Compression of the optic chiasm
25. Abnormal free T4. Subjects with TSH <LLN and normal free T4 are permitted to participate in the study.
26. Subjects who have a history of alcohol or drug abuse in the 6 month period prior to enrollment.
27. The subject is currently taking any H2 receptor antagonists or proton-pump inhibitors (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.
28.The subject is receiving the following concomitant therapies:
•Weight loss medications (prescription or over the counter)
•Coadministration of COR-003 and drugs primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentrations of the drugs that could increase or prolong both therapeutic and/or adverse effects.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| •Response to COR-003, defined as a reduction in mean UFC levels ≤ULN following 6 months of maintenance phase therapy without a prior dose increase during that phase |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Following 6 months of maintenance phase therapy |
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| E.5.2 | Secondary end point(s) |
•Response to COR-003, defined as mean UFC level ≤ULN at 1, 2, 3, 4 and 5 months of dosing in the maintenance phase and at 9 and 12 months in the extended evaluation phase
•Response to COR-003, defined as UFC level ≤ULN or ≥ 50% reduction from baseline following 1, 2, 3, 4, 5 and 6 months of dosing in the maintenance phase and at 9 and 12 months in the extended evaluation phase
•Mean UFC concentrationslevels at 1, 2, 3, 4, 5 and 6 months of dosing in the maintenance phase and at 9 and 12 months in the extended evaluation phase, including percent change from baseline
•Proportion of subjects with a reduction ofin UFC concentrationslevels from baseline at 1, 2, 3, 4, 5 and 6 months of dosing in the maintenance phase and at 9 and 12 months in the extended evaluation phase
•Shift in UFC normality at 1, 2, 3, 4, 5 and 6 months of dosing in the maintenance phase and at 9 and 12 months in the extended evaluation phase
•Mean plasma and late night salivary cortisol levels at 1, 2, 3, 4, 5 and 6 months of dosing in the maintenance phase and at 9 and 12 months in the extended evaluation phase
•Changes in clinical signs and symptoms (systolic and diastolic blood pressure, body weight/mass index, abdominal girth, body habitus and physical appearance, CushingQoL questionnaire scores, etc.)
•Changes in ambulatory blood pressure monitoring (ABPM) from baseline at each post-dose timepoint
•Changes in biochemical markers from baseline at 3 and 6 months of dosing during the maintenance phase and at 9 and 12 months during the extended evaluation phase for the following: lipid profile (to include triglycerides, total HDL/LDL cholesterol, lipid ratios), fasting bloodserum glucose levels, hemoglobin A1CA1c (HbA1c), oral glucose tolerance test (pre-diabetics only), CRP, spot albumin/creatinine ratios (as a measure of microalbuminuria), ACTH, IGF-1 and testosterone concentrations (females only)
•Changes in the doses of anti-diabetic and antihypertensive medication use prior to andmedications following 6 months of dosing with COR-003 during the maintenance phase relative to baseline doses
•PK model parameters will be estimated (when possible) using population PK modeling and will include: clearance (CL/F), volume of distribution (V/F), absorption rate constant (Ka) with associated between subject variability where feasible, including derived parameters of half-life (t½), area under the concentration time curve (AUC) and peak concentration (Cmax) will be reported, if appropriate.). Because the pharmacokinetics of COR -003 are reported to change over time, time dependent changes in CL/F, AUC and t½ will be investigated, and if identified, will be incorporated into the model.
•The PD model parameters will be estimated and will include: COR-003 dose that produces maximal suppression of UFC (Imax), concentrationdose producing half maximal UFC suppression (IC50) and associated estimates of between subject variability. The range of UFC reduction by dose will be explored.
•Safety evaluations will include clinical observations and adverse event (AE) reporting; physical examinations inclusive of vital signs (systolic and diastolic blood pressure, body weight, body mass index), hematology, chemistry panels (inclusive of expanded markers of liver function, serum cortisol and testosterone [males only] concentrations), dipstick urinanalyisurinalysis (microscopic evaluation, if dipstick positive) and IGF-1 concentrations.
•Electrocardiograms (ECGs) will be evaluated. The relationship of QTc to dose (exposure) of COR-003 will be describedevaluated, as data permit.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Depending on criteria being measured. 1, 2, 3, 4, 5 & 6 months in maintenance phase. 9 and 12 months in extended evaluation phase. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| Denmark |
| France |
| Georgia |
| Germany |
| Israel |
| Italy |
| Netherlands |
| Spain |
| Sweden |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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