E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Endogenous Cushing syndrome |
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E.1.1.1 | Medical condition in easily understood language |
Cushing Syndrome caused by the body producing more cortisol than it needs
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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 | 24.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10011657 |
E.1.2 | Term | Cushings syndrome |
E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
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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 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 |
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E.2.2 | Secondary objectives of the trial |
• 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 nigth 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 |
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E.4 | Principal 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 hypersensitivity or severe reaction to the study drug, to a similar class of drug, or to the study drug's excipient. 26. In the Investigator's opinion, should not participate in the study or may not be capable of following the study schedule. 27. Has known HIV or hepatitis B or C infection. 28. Is a family member of one of the Sponsor's employees, the Investigator, or the site staff directly working on the study. 29. Has a history of unexplained vaginal bleeding or unexplained endometrial abnormalities. |
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E.5 End points |
E.5.1 | 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) |
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E.5.1.1 | 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 |
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E.5.2 | 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 a 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).
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E.5.2.1 | 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, haematology, chemistry: OL22, every 4 weeks in the RW phase •HbA1c: OL22 and RW12 •Concomitant medication, OL22, every 4 weeks in the RW 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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Open-label dose-escalation phase (22-26wks) then a double-blind randomized withdrawal phase (12wks) |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 35 |
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 |
Colombia |
Canada |
Israel |
United States |
Austria |
Bulgaria |
Germany |
Italy |
Netherlands |
Poland |
Romania |
Spain |
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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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The end of study is defined as the date of last contact (visit, telephone, e-mail) with any study patient. |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 12 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
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 |