| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Endogenous Cushing’s Syndrome |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cushing's syndrome caused by the body producing more cortisol than it needs |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Physiological processes [G07] |
| 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 |
|
| 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 assess the safety and efficacy of CORT125134 in patients with endogenous Cushing’s syndrome. |
|
| E.2.2 | Secondary objectives of the trial |
| To assess the evidence of reduction in cortisol activity following treatment with CORT125134 in patients with endogenous Cushing’s syndrome based on improvement in blood glucose control and/or blood pressure (BP). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Is a male or female adult, 18–80 years of age
2. Has a diagnosis of endogenous Cushing's syndrome confirmed by:
At least two of the following test criteria (Nieman 2008):
•Urinary free cortisol above the upper limit of normal (ULN) (50.0 μg/24h) in at least 2, and up to 4, complete 24 hour collections within 3 weeks prior to Day 1 (baseline)
•Late-night salivary cortisol above the ULN (at least 2, and up to 4,
collections using a salivette) within 3 weeks prior to Day 1 (baseline)
•Lack of cortisol suppression (>1.8 μg/dL serum cortisol) on either 1 mg overnight or 2-mg 48 hour dexamethasone suppression testing during screening or within 12 weeks before the ICF is signed.
And
At least two of the following clinical signs and symptoms of Cushing’s syndrome:
•Facial characteristics of a Cushingoid appearance (moon facies, dorsocervical fat pad, plethora)
•Increased body weight or central obesity
•Proximal muscle weakness
•Low bone mass (dual energy X-ray absorptiometry [DXA] T < −1.0)
•Psychiatric symptoms (including depression or psychosis)
•Hirsutism and/or violaceous striae and/or acne
•Easy bruising
A patient with an adrenal lesion may alternatively qualify if there is
autonomous cortisol secretion based on dexamethasone suppression
testing (Fassnacht 2016) and supporting evidence of clinically significant cortisol excess. Such a patient must have:
• Radiologically proven unilateral or bilateral adrenal disease (nodules, hyperplasia)
• Lack of cortisol suppression (>5 μg/dL serum cortisol) on either 1-mg overnight or 2-mg 48-hour dexamethasone suppression testing during screening
• Low or suppressed ACTH (<10 pg/mL) to confirm ACTH-independency
• Presence of at least two comorbidities potentially related to cortisol
excess (eg, type 2 diabetes, hypertension, obesity, osteoporosis), of
which at least one is inadequately controlled by medical measures
3. Requires medical treatment of hypercortisolemia (i.e. those for whom surgery or radiation is contraindicated or has been refused)
Examples include, but are not limited to, patients with Cushing’s disease who are post-surgery and/or post-radiation for whom additional surgery is not recommended; de novo patients with Cushing’s disease who are not eligible for surgery due to comorbidities; and patients with ectopic ACTH-dependent Cushing’s syndrome in which the tumor cannot be localized or completely removed.
4. Meets at least one of the following criteria:
•Has type 2 diabetes mellitus as confirmed at screening visit with a fasting glucose >126 mg/dL and a 2-hour oral glucose tolerance test [oGTT] result for plasma glucose ≥200 mg/dL at 2 hours (Standards of Medical Care in Diabetes – 2015)
•Has impaired glucose tolerance (2-hour oGTT result for plasma glucose in the range of ≥140 mg/dL to <200 mg/dL) (Standards of Medical Care in Diabetes – 2015)
• Has hypertension (mean systolic BP of 130–170 mmHg and/or a mean diastolic BP of
85–110 mmHg) based on 24 hour ambulatory BP measurement (O’Brien 2013)
5. If taking antidiabetic medication, is on a stable dose (i.e. cannot start new medication or change dose within 4 weeks prior to the first dose of study drug)
6. If taking antihypertensive medication, is on a stable dose (i.e. cannot start new medication or change dose within 4 weeks prior to the screening ambulatory BP measurement)
7. Has potassium within the normal range (3.5–5.3 mEq/L) at screening or corrected to within the normal range by Day 1
8. Female patients of childbearing potential must be willing to use a highly effective method of contraception from 30 days prior to Day 1 until 30 days after the last dose of study drug. Male patients with a female partner must agree to 2 forms of contraception, one of which must be a double-barrier method, from Day 1 until 30 days after the last dose of study drug. Highly effective methods of contraception include true abstinence (refraining from heterosexual intercourse during the entire period of risk associated with the study treatments when this is in line with the preferred and usual lifestyle of the subject), oral contraceptives plus barrier method, diaphragm with vaginal spermicide, intrauterine device, condom and partner using vaginal spermicide, and surgical sterilization (≥6 months post-surgery).
9. (Female patients): Has a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline (Day 1)
10. Has a life expectancy of at least 6 months
11. Is able to participate in the study for up to 22 weeks in Group 1 and 26 weeks in Group 2, including returning to the investigative site to fulfill the safety and efficacy evaluations outlined in the protocol
12. Is able to read and understand the consent form and communicate with the study staff
13. Provides written consent to participate in the study prior to any study procedures and understands that he/she is free to withdraw from the study at any time
|
|
| E.4 | Principal exclusion criteria |
1. Has a non-endogenous source of hypercortisolemia
2. Has pseudo-Cushing’s syndrome. Patients with known or suspected pseudo-Cushing’s syndrome based on medical history (such as patients with severe obesity, major depression, or a history of alcoholism) should undergo a dexamethasone-CRH/DDAVP stimulation test (Yanovski 1993, Giraldi 2007, Yanovski 1998) to rule-in or rule-out this possibility.
3. Has uncontrolled, clinically significant hypothyroidism or hyperthyroidism
4. Has poorly controlled hypertension, defined as systolic BP >170 mmHg or diastolic BP >110 mmHg at screening
5. Has Stage 4 renal failure (ie, glomerular filtration rate ≤29 mL/min)
6. Has elevated total bilirubin >1.5×ULN or elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3×ULN
7. For patients with diabetes or abnormal oGTT at screening: Has
glycated hemoglobin (HbA1c) of >12% within 3 months of first dose of
study drug
8. Has a screening hemoglobin level of <9 g/dL
9. Has a clinically significant electrocardiogram (ECG) abnormality at screening, which, in the opinion of the Investigator, will make the patient an unsuitable candidate for the study
10. Has a confirmed screening QTcF interval >450 ms for males and >470 ms for females (using Fridericia’s correction) in the presence of a normal QRS interval (QRS <120 ms) or a history of additional risk factors for torsades de pointes
11. Is currently receiving chemotherapy for a tumor related to Cushing’s syndrome
12. Had radiation therapy for Cushing’s syndrome-related tumor within 1 year of screening period
13. Is planning surgery or radiation therapy for Cushing’s syndrome-related tumor during the study
14. Has used or plans to use any of the following treatments for Cushing’s syndrome, as specified:
•Adrenostatic medications: metyrapone, ketoconazole, fluconazole, aminoglutethimide, or etomidate from 4 weeks prior to baseline (Day 1) through the follow-up visit
•Adrenolytic medications:
oIn Group 1, any patients taking mitotane
oIn Group 2 only, patients with adrenocortical carcinomas taking mitotane whose dose has not been stable for at least 2 months prior to baseline (Day 1) or in whom increases in the mitotane dosage are expected through the end of dosing
•Neuromodulator drugs that act at the hypothalamic-pituitary level: serotonin antagonists (cyproheptadine, ketanserin, retanserin), dopamine agonists (bromocriptine, cabergoline), gamma-aminobutyric acid agonists (sodium valproate), and somatostatin receptor ligands (octreotide long-acting release [LAR], pasireotide LAR, lanreotide) from 8 weeks before baseline (Day 1) through the follow-up visit. Use of short-acting somatostatin analogs (octreotide, pasireotide) from 4 weeks prior to baseline (Day 1) through the follow-up visit.
•Mifepristone, from 6 weeks before baseline (Day 1) through the follow-up visit
15. Has started or increased (or plans to start or increase) the dose of an antidepressant medication (eg, selective serotonin reuptake inhibitors or tricyclic compound) from 6 weeks before baseline (Day 1) through the end of the study dosing period
16. Has started or increased (or plans to start or increase) the dose of a lipid-lowering drug from 4 weeks before baseline (Day 1) through the follow-up visit
17. Is lactating
18. Has an acute or unstable medical problem that could be aggravated by treatment with the investigational study drug
19. Has a history of hypersensitivity or severe reaction to the study drug, to a similar class of drug, or to the study drug’s excipients
20. Has taken any investigational drug within 30 days before baseline (Day 1), or within a period of less than five times the drug’s half life, whichever is longer
21. In the Investigator’s opinion, should not participate in the study or may not be capable of following the study schedule
22. Has known HIV or hepatitis B or C infection
23. Is a family member of one of the Sponsor’s employees, the Investigator, or the site staff directly working on the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Key Efficacy:
•Oral glucose tolerance test (oGTT) (impaired glucose tolerance/diabetes subgroup only)
•Ambulatory BP measurement (hypertension subgroup only)
Pharmacokinetics:
•Blood levels of CORT125134 and metabolites
Safety:
•Physical examination findings, vital signs, ECG results, pregnancy tests, clinical laboratory test results (hematology and chemistry panels), adverse events (AEs), and concomitant medications |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
•oGTT at baseline (Day 1) and Week 4, Week 8, and Week 12/early termination (ET) visits.
•Ambulatory BP for all at screening. For hypertension subgroup baseline, weeks 2, 4, 6, 8, 10, and 12/ET
•Pharmacokinetics will be measured predose and at 1, 2, 4, 6, and 8 hours postdose at Weeks 2, 6, and 10, and predose only at Weeks 4, 8, and 12/early termination
•Safety assessments performed at baseline (Day 1), Week 2, Week 4, Week 6, Week 8, Week 10, and Week 12/ET visits and follow-up. |
|
| E.5.2 | Secondary end point(s) |
Exploratory efficacy assessments
•Physician’s Global Assessment
•HbA1c
•Fructosamine
•Adiponectin
•24-hour urinary free cortisol (UFC) with creatinine
•Late-night salivary cortisol
•Body weight, waist circumference
•Beck Depression Inventory (BDI-II), Trail Making Test, CushingQoL
•Lipid panel
•Sit-to-stand test
•Sex hormone levels
•Menstrual cycle characterization (premenopausal women not on hormonal birth control)
•Coagulation tests
•Glucocorticoid receptor (GR) biomarker tests
•Bone markers (serum bone alkaline phosphatase, osteocalcin, urine N telopeptides of type 1 collagen [NTx], calcium from 24-hour UFC)
•Hypothalamic-pituitary-adrenal (HPA) axis markers, including plasma
ACTH and serum cortisol concentrations
•ACTH precursors
•High-sensitivity C-reactive protein concentrations
•24-hour urine calcium and sodium
•Insulin-like growth factor (IGF-1)
•Thyroid function tests |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At baseline, Weeks 2, 4, 6, 8, 10, 12/ET, and follow-up |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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.8.3 |
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 |
|
| 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
|
|
| 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 | 5 |
| 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 | 5 |
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