A study to assess whether a product called relacorilant works and is safe to use in patients with Cushing Syndrome; some patients will receive relacorilant whilst others receive a placebo.

• Register: EUCTR
• Last refreshed on: 15 July 2024
• Main ID: EUCTR2018-003096-35-NL
• Date of registration: 11/12/2018
• Prospective Registration: Yes
• Primary sponsor: Corcept Therapeutics Incorporated
• Public title: A study to assess whether a product called relacorilant works and is safe to use in patients with Cushing Syndrome; some patients will receive relacorilant whilst others receive a placebo.
• Scientific title: Glucocorticoid Receptor Antagonism in the Treatment of Cushing Syndrome (GRACE): A Phase 3, Double-Blind, Placebo-Controlled, Randomized-Withdrawal Study of the Efficacy and Safety of Relacorilant - CORT125134-455
• Date of first enrolment: 19/06/2019
• Target sample size: 162
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-003096-35
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: yes Other trial design description: Open-label dose-escalation phase (22-26wks) then a double-blind randomized withdrawal phase (12wks) If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Bulgaria, Canada, Germany, Israel, Italy, Netherlands, Poland, Romania, Spain, United States

Contacts

• Name: Clinical Operations
• Affiliation: Corcept Therapeutics Incorporated

• Name: Clinical Operations
• Affiliation: Corcept Therapeutics Incorporated

Key inclusion & exclusion criteria

Inclusion criteria:
To enroll in the study, each patient must meet the following key inclusion criteria:
1. Male or female, 18 to 80 years of age, inclusive
2. Has a confirmed biochemical diagnosis of endogenous Cushing syndrome based on the presence of at least 2 of the following:
• UFC > upper limit of normal (ULN) in at least 2 complete 24-hour tests within the screening window.
• Late-night salivary cortisol >ULN in at least 2 tests (using a salivette) within the screening window (Note: Test is not appropriate for night shift workers and cannot be used to evaluate eligibility)
• 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 signing the informed consent
3. Has at least 2 of the following clinical signs and symptoms of Cushing syndrome:
• Bodily characteristics of a Cushingoid appearance (e.g., facial rubor, moon facies, dorsocervical fat pad, supraclavicular fat pad)
• Increased body weight or central obesity
• Proximal muscle weakness
• Low bone mass based on DXA scan
• Psychiatric symptoms (including depression or psychosis)
• Skin manifestations: violaceous striae, acne, and/or hirsutism
• Easy bruisability
4. Has at least 1 of the following at Baseline:
• DM (fasting plasma glucose =126 mg/dL and/or 2-hour oGTT plasma glucose =200 mg/dL at 2 hours or HbA1c = 6.5%), or IGT (plasma glucose =140 mg/dL and <200 mg/dL on a 2-hour oGTT glucose)
• Uncontrolled hypertension (mean SBP =135 to =170 mm Hg and/or mean DBP =85 to =110 mm Hg) based on 24-hour ABPM
5. If receiving medical treatment for DM/IGT or hypertension, there has been no increase in medication dosage for at least 4 weeks prior to Baseline assessment
6. If receiving medical treatment for depression, there has been no increase in medication dosage for at least 6 weeks prior to Baseline
7. For women of childbearing potential, has a negative serum pregnancy test at Screening and negative urine pregnancy test at Baseline
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 146
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 16

Exclusion criteria:
Patients who meet any of the following criteria will not be permitted entry to the study:
1. Has severe, uncontrolled hypertension (mean SBP >170 mm Hg or mean DBP >110 mg at Screening), based on 24-hour ABPM
2. Has poorly controlled DM (HbA1c >12% at Screening)
3. Has a known "long term" history of both hypertension and diabetes (defined as both hypertension and diabetes diagnosed >10 years prior to the initial diagnosis of endogenous CS)
4. Has a history of cyclic Cushing's syndrome with fluctuating clinical manifestations.
5. Has DM Type 1.
6. Has abnormal liver test results (total bilirubin >1.5×ULN or elevated alanine aminotransferase or aspartate aminotransferase >3×ULN at
Baseline)
7. Has severe renal insufficiency (glomerular filtration rate =29 mL/min at Baseline)
8. Has uncontrolled, clinically significant hypothyroidism or
hyperthyroidism
9. Has prolonged QT interval corrected for heart rate using Fridericia's equation (QTcF) (>450 ms for men and >470 ms for women) with
normal QRS interval (<120 ms) or QTcF interval >500 ms with wide QRS interval (=120 ms)
10. Has received stereotactic radiation therapy for a Cushing syndromerelated tumor within 24 months of Baseline or conventional pituitary radiation therapy within 36 months of Baseline.
11. Has undergone pituitary surgery <3 months prior to Screening.
12. Has used or plans to use any of the following treatments for Cushing syndrome within 4 weeks prior to Baseline:
• Mifepristone
• Adrenostatic medications: metyrapone, osilodrostat, ketoconazole, fluconazole, aminoglutethimide, or etomidate
• Serotonin antagonists: cyproheptadine, ketanserin, or ritanserin
• Dopamine agonists: bromocriptine or cabergoline
• Gamma-aminobutyric acid agonists: sodium valproate
• Short-acting somatostatin analogs: octreotide, lanreotide, or
pasireotide
13. Has used or plans to use somatostatin receptor ligands: long-acting octreotide or pasireotide within 8 weeks prior to Baseline
14. Patients who require inhaled glucocorticoid use and have no
alternative option if their condition deteriorates during the study.
15. Has adrenocortical carcinoma.
16. Has used mitotane prior to Baseline
17. Has ectopic Cushing syndrome and a life expectancy of <3 years or receiving chemotherapy.
18. Has pseudo-Cushing syndrome. Patients with known or suspected pseudo-Cushing syndrome based on medical history (such as patients with severe obesity, major depression, or a history of alcoholism) should undergo a dexamethasone-CRHDDAVP stimulation test to rule-in or ruleout this possibility
19. Has taken any investigational drug within 4 weeks prior to Baseline,
or within less than 5 times the drug's half-life, whichever is longer
20. Ongoing use of antidiabetic, antihypertensive, antidepressant, or lipid-lowering medications that are highly dependent on CYP3A for clearance and that cannot undergo dose modification upon
coadministration with strong CYP3A inhibitors
21. Ongoing use of any strong CYP3A4 inducer or any other prohibited medications
22. Is pregnant or lactating
23. Is a female patient of childbearing potential (including all women <50 years old, women whose surgical sterilization was performed <6 months ago, and women who have had a menstrual period in the last 2 years) who cannot use a highly effective method of contraception.
24. Has an acute or unstable medical problem that could be aggravated by treatment with the investigational study drug
25. Has a history of hy

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

Health Condition(s) or Problem(s) studied

Endogenous Cushing syndrome
MedDRA version: 24.0 Level: LLT Classification code 10011657 Term: Cushings syndrome System Organ Class: 10014698 - Endocrine disorders

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

Intervention(s)

Product Name: Relacorilant
Product Code: CORT125134
Pharmaceutical Form: Capsule, soft
INN or Proposed INN: Relacorilant
CAS Number: 1496510-51-0
Other descriptive name: (R)-(1-(4-FLUOROPHENYL)-6-((1-METHYL-1H-PYRAZOL-4YL)SULFONYL)4,4A,5,6,7,8-HEXAHYDRO-1H-PYRAZOLO[3,4-G]ISOQUINOLIN-4A-YL)(4-(TRIFLUOROMETHYL)PYRIDIN-2-YL)METHANONE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Capsule, soft
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: • To assess changes in cortisol excess-related comorbidities (including DM/IGT and body weight) in patients with endogenous Cushing syndrome treated with relacorilant over the RW phase

Main Objective: • To assess the efficacy of relacorilant for the treatment of endogenous Cushing syndrome based on BP control at Week 12 of the Randomized-Withdrawal (RW) phase compared with placebo
• To assess the safety of relacorilant for the treatment of endogenous Cushing syndrome

Primary end point(s): The primary efficacy endpoint will be assessed in the RW phase. The study will be considered to have a positive outcome if the primary efficacy endpoint reaches statistical significance:
• In patients with hypertension, the proportion of patients with a loss of response with respect to hypertension from Visit OL22 to RW12 based on 24-hour ABPM as compared between relacorilant and placebo arms, where loss of response is defined as follows:
– In patients who met only the SBP response criterion, an increase in SBP =5 mm Hg
– In patients who met only the DBP response criterion, an increase in DBP by =5 mm Hg
– In patients who met both the SBP and DPB response criteria, an increase in either SBP or DBP by =5 mm Hg
– Any increase or modification in antihypertensive medication due to worsening hypertension.
• Patients discontinue treatment in RW phase for any reason.
• In all patients, assessment of safety based on treatment-emergent adverse events (TEAEs)

Timepoint(s) of evaluation of this end point: •AE: screening, baseline, every 4 weeks
•ABPM: OL22, every 4 weeks in the RW phase
•Concomitant medication, OL22, every 4 weeks in the RW phase

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: •ABPM: OL22 and RW12
•oGTT: OL22, every 4 weeks in the RW phase
•body weight, vital signs, hematology, chemistry: OL22, every 4 weeks in the RW phase
•HbA1c: OL22 and RW12
•Concomitant medication, OL22, every 4 weeks in the RW phase

Secondary end point(s): Secondary Efficacy Endpoints in the Randomized-Withdrawal Phase

• Mean change from Visit OL22 to RW12 in 24-hour average SBP as compared between relacorilant and placebo
• Mean change from Visit OL22 to RW12 in 24-hour average DBP as compared between relacorilant and placebo
• Mean change from Visit OL22 to RW12 in body weight as compared between relacorilant and placebo
• In patients with DM/IGT, the mean change in AUCglucose from Visit OL22 to RW12 as compared between relacorilant and placebo arms.
• For patients in the DM/IGT subgroup with response at OL22, the proportion of patients with a loss of response with respect to hyperglycemic control from Visit OL22 to RW12, as compared between relacorilant and placebo arms, where loss of response is defined as follows:
In patients with DM:
– Use of rescue medication (initiation or increase in diabetes medication due to worsening of hyperglycemic control), treatment discontinuation for any reason in RW phase, or loss to follow-up,
OR
– HbA1c has increased by =0.3% at Visit RW12 (compared to OL22),
OR
– The 2-hour time point of the plasma 2-hours oGTT glucose test at Visit RW12 is abnormal (=140 mg/dL) and has increased by at least 50% of the reduction observed between Baseline and Visit OL22.
In patients with IGT:
– Use of rescue medication (initiation or increase in diabetes medication due to worsening of hyperglycemic control), treatment discontinuation for any reason in RW phase, or loss to follow-up,
OR
– The 2-hour time point of the plasma 2-hour oGTT glucose test at Visit RW12 is abnormal (=140 mg/dL) and has increased by at least 50% of the reduction observed between Baseline and Visit OL22.
• For patients in the DM/IGT subgroup with response at OL22, the proportion of patients with a loss of response with respect to hyperglycemic control from Visit OL22 to RW12, as compared between
relacorilant and placebo arms, where loss of response is defined as follows:
– Use of rescue medication (initiation or increase in diabetes medication due to worsening of hyperglycemic control), treatment discontinuation for any reason in RW phase, or loss to follow-up,
OR
– HbA1c has increased by =0.3% at Visit RW12 (compared to OL22).

Secondary ID(s)

NCT03697109

CORT125134-455

Source(s) of Monetary Support

Corcept Therapeutics Incorporated

Ethics review

Status: Approved
Approval date: 19/06/2019
Contact: