Clinical trial to assess the safety and effectiveness of a study drug called "CORT125134" in the treatment of Cushing's syndrome

• Register: EUCTR
• Last refreshed on: 28 February 2019
• Main ID: EUCTR2016-000899-23-GB
• Date of registration: 21/06/2016
• Prospective Registration: Yes
• Primary sponsor: Corcept Therapeutics Incorporated
• Public title: Clinical trial to assess the safety and effectiveness of a study drug called "CORT125134" in the treatment of Cushing's syndrome
• Scientific title: Phase 2 Study of the Safety and Efficacy of CORT125134 in the Treatment of Endogenous Cushing’s Syndrome
• Date of first enrolment: 16/08/2016
• Target sample size: 30
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-000899-23
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Hungary, Netherlands, United Kingdom, United States

Contacts

• Name: CORT451 Project Manager (11598)
• Affiliation: Chiltern International Ltd

• Name: CORT451 Project Manager (11598)
• Affiliation: Chiltern International Ltd

Key inclusion & exclusion criteria

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 o
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

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Endogenous Cushing’s Syndrome
MedDRA version: 20.0 Level: LLT Classification code 10011657 Term: Cushings syndrome System Organ Class: 100000004860

Therapeutic area: Body processes [G] - Physiological processes [G07]

Intervention(s)

Product Code: CORT125134
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Relacorilant
CAS Number: 1496510-51-0
Current Sponsor code: CORT125134
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Primary Outcome(s)

Secondary Objective: 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).

Main Objective: To assess the safety and efficacy of CORT125134 in patients with endogenous Cushing’s syndrome.

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

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.

Secondary Outcome(s)

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

Timepoint(s) of evaluation of this end point: At baseline, Weeks 2, 4, 6, 8, 10, 12/ET, and follow-up

Secondary ID(s)

CORT125134-451

IND Number

Source(s) of Monetary Support

Corcept Therapeutics Incorporated

Ethics review

Status: Approved
Approval date:
Contact: