E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Endogenous Cushing's syndrome (CS) or Cushing's disease |
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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 | 20.0 |
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 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. |
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E.2.2 | Secondary objectives of the trial |
• To identify the proportion of subjects with clinical response, defined as reduction in mean 24-hour UFC levels to below or equal to the upper limit of normal (≤ ULN) after each month of treatment with COR-003 without a dose increase during the Maintenance Phase; • To identify the proportion of subjects with complete or partial response, defined as ≥50% reduction of 24-hour UFC levels from Baseline after each of the 6 months of treatment with COR-003 without a dose increase during the Maintenance Phase; • To characterize changes in 24-hour UFC levels from Baseline during the 6 months of treatment with COR-003 in the Maintenance Phase regardless of dose increases; • To characterize shifts in normality for 24-hour UFC levels from Baseline during the 6 months of treatment with COR-003 in the Maintenance Phase regardless of dose increases;
For all other secondary objectives, please refer to the protocol.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 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 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 In the absence of pathological or post-surgical confirmation of the diagnosis of CD (i.e. documented adrenal insufficiency post- adenomectomy or hypophysectomy, which will be considered diagnostic). The following historical evidence will be considered satisfactory to establish the diagnosis of CD: • Plasma corticotropin (ACTH) level >20 pg/mL (4.5 pmol/L) or greater (Note: ACTH ≥5 pg/mL (1.1 pmol/L) and ≤20 pg/mL will generally suffice only if accompanied by either a positive CRH stimulation test or DST or combined CRH-DST) PLUS one of the diagnostic strategies described below based on pituitary MRI/computed tomography (CT) findings (Note: pituitary imaging preceding the original diagnosis is a requirement for eligibility): • For tumors ≥6 mm by imaging: − Inferior petrosal sinus sampled (IPSS) ACTH central:plasma gradient ≥2 before CRH or ≥3 after CRH, OR if IPSS was not done then: − Positive ACTH and/or cortisol response to CRH/desmopressin or combined CRH-desmopressin stimulation plus high-dose (8 mg) dexamethasone suppression of plasma cortisol, ideally on more than one occasion, performed and interpreted according to internationally recognized standards of diagnosis − In the absence of IPPS and the combination of tests described, 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. • For tumors <6 mm or not visible by MRI: − IPSS with ACTH central:plasma gradient ≥2 before CRH or ≥3 after CRH − 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. Regardless of the etiology of endogenous CS, subjects 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. Urine will ideally be collected on sequential days. 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 μg/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 NOTE: For subjects with estimated glomerular filtration rate (eGFR as determined by Modified Diet in Renal Disease MDRD equation) >40 and <60 mL/min/1.73 m2 in addition to meeting the UFC criteria, late night salivary cortisol test results (≥2 measurements) MUST also demonstrate evidence of CS. 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. For subjects who have already undergone surgery, a minimum of 6 weeks should have elapsed before the subject can be deemed a surgical failure. Subjects who have undergone surgery should be stable post-surgery (i.e., no significant post-operative sequelae remain and the risk of such sequelae is considered negligible).
For all other inclusion criteria, please refer to the protocol.
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E.4 | Principal exclusion criteria |
1. Subjects with Pseudo-CS 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. Subjects with history of such allowed carcinoma must have a life expectancy of >18 months and must be considered medically stable. Subjects with early stage prostate cancer undergoing no treatment due to low grade potential may be enrolled 7. Clinical or radiological signs of compression of the optic chiasm 8. Major surgery within 1 month prior to enrollment 9. Subjects with clinically significant abnormality in 12-lead ECGs during the Screening Phase needing medical intervention 10. Subjects with QTc interval of >470 msec during the Screening Phase 11. Subjects with a 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. 12.Pre-existing hepatic disease; subjects with mild to moderate hepatic steatosis consistent with fatty infiltration (non-alcoholic fatty liver disease [NAFLD] are allowed) 13. Positive for HbsAg or positive HBC test. 14. History or symptoms of recurrent symptomatic cholelithiasis or pancreatitis 15. LFT must not be above the following cut-offs during the Screening Phase: • ALT and/or AST >3 X ULN • Total bilirubin (TBN) >2 X ULN If all LFTs are within normal limits and TBN is elevated, examination of direct and indirect bilirubin may be conducted. Subjects with isolated indirect TBN up to 3X ULN are presumed to have Gilbert's syndrome and may be enrolled if all other LFTs are within normal levels 16. History of documented or suspected drug-induced liver injury requiring drug discontinuation of ketoconazole or any azole antifungals 17. Pregnant or lactating women 18. HIV positive 19. History of persistent uncontrolled hypertension (>180/120 mmHg) despite medical intervention. 20. Subjects with hypercholesterolemia currently treated with atorvastatin, lovastatin or simvastatin and not willing or unable to change to alternative therapies i.e. pravastatin, fluvastatin, or rosuvastatin within 2 weeks of start of the Screening Phase. 21. Body habitus preventing repeated venipuncture as required by protocol. 22. Subject is currently in another study or has received any investigational treatment (drug, biological agent or device) within 30 days or five half-lives of treatment, whichever is longer. 23. Repeated hospitalization for hyperglycemia or for any complication of hyperglycemia and diabetes during the last 12 months 24. Subjects with decreased renal function as defined by eGFR <40 mL/min/1.73 m2, using MDRD equation. 25. 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 to perform the necessary procedures 26. Abnormal FT4. Subjects with TSH below the lower limit of normal (<LLN) and normal free T4 are permitted to participate in the study. 27. Subjects who have a history of alcohol or drug abuse in the 6 month period prior to enrollment. 28. Subjects who have been treated with mitotane within 6 months of the Screening Phase. 29. Subjects who are currently taking any H2 receptor antagonists, proton-pump inhibitors, or sucralfate (all of 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. 30. Subjects who receive any prohibited concomitant medication and cannot discontinue it safely prior to the Baseline Visit: • Weight loss medications (prescription or over the counter) • Acetaminophen (paracetamol) >3 g total daily dose • Strong inducers or inhibitors of CYP3A4 enzyme system that may interfere with the metabolism of COR-003 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 tangand Salboku-to). • Topical or inhaled corticosteroids • Carbamazepine, fenofibrate, carbenoxolone. • Drugs that might pose unacceptable risks due to overlapping toxicities (eg. QT prolongation, liver toxicity); • Genuine licorice
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of subjects with response to COR-003, defined as reduction in mean 24-hour UFC levels to below or equal to the upper limit of normal (≤ ULN) following 6 months of Maintenance Phase therapy without a dose increase during that phase, summarized by Maintenance Phase dose level and overall.
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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) |
• Proportion of subjects with clinical response to COR-003, defined as mean UFC level ≤ ULN, to be determined after 1, 2, 3, 4 and 5 months of dosing without a dose increase in the Maintenance Phase; • Proportion of subjects with complete or partial response to COR-003, defined as mean UFC level ≥ 50% reduction from Baseline after 1, 2, 3, 4, 5 and 6 months of dosing without a dose increase in the Maintenance Phase; • Change and percentage change from Baseline in mean 24-hour UFC levels after 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase regardless of dose increases; • Shift in UFC normality categories from Baseline to 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase regardless of dose increases; • Change and percentage change from Baseline in serum and late night salivary cortisol levels after 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase; • Changes from Baseline in Clinical Signs and Symptoms of CS after 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase; • Changes from Baseline in the QoL measures obtained from the Cushing QoL questionnaire and the severity of depression obtained from the Beck's Depression Inventory II after 3 and 6 months of dosing in the Maintenance Phase; • Change from Baseline in CS comorbidities biomarkers (fasting glucose, hemoglobin A1C [HbA1c], systolic blood pressure [SBP], diastolic blood pressure [DBP], total cholesterol, low and high density lipoproteins [LDL, HDL, respectively], and body weight) after 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase; • Changes from Baseline for oral glucose tolerance test (OGTT) (pre- diabetics only) and spot albumin/creatinine ratio as a measure of microalbuminuria (only if abnormal at Baseline) after 3 and 6 months of dosing in the Maintenance Phase; • Changes from Baseline for C-reactive protein (CRP) after 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase; • Safety evaluations will include clinical observations and adverse event (AE) reporting, vital signs (SBP, DBP, body weight, body mass index [BMI]), electrocardiograms (ECGs), hematology, chemistry panels (inclusive of expanded markers of liver function, ACTH, Insulin-like Growth Factor-1 (IGF-1) and testosterone concentrations), dipstick urinalysis (microscopic evaluation, if dipstick positive), tumor size by magnetic resonance imaging (MRI) as applicable.
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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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 59 |
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 |
Bulgaria |
Canada |
Czech Republic |
Denmark |
France |
Georgia |
Germany |
Hungary |
Israel |
Italy |
Netherlands |
Poland |
Romania |
Serbia |
Spain |
Sweden |
Turkey |
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 | 6 |
E.8.9.1 | In the Member State concerned days | |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |