| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Endogenous Cushing syndrome |
|
| E.1.1.1 | Medical condition in easily understood language |
Cushing 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 | 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 | 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 efficacy of relacorilant for the treatment of endogenous Cushing syndrome based on glycemic control and 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
|
|
| E.2.2 | Secondary objectives of the trial |
| • To assess changes in cortisol excess-related comorbidities (including diabetes mellitus/impaired glucose tolerance and hypertension, quality of life, body weight, and Global Clinical Response) in patients with endogenous Cushing syndrome treated with relacorilant over the Open-Label (OL) and RW phases |
|
| 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 > the upper limit of normal (ULN) in at least 2 complete 24-hour tests within the 4 weeks prior to Baseline
• Late-night salivary cortisol >ULN in at least 2 tests (using a salivette) within the 4 weeks prior to Baseline (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 |
|
| 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 syndrome-related 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
18. Has pseudo-Cushing syndrome. Patients with known or suspected pseudo-Cushingsyndrome 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 rule-out 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 inhibitor/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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Endpoints for both OL and RW phases are listed below. In the RW phase, (1) endpoints related to DM/IGT will be analyzed in those patients who met any response criterion for DM/IGT at Visit OL22; and (2) endpoints related to hypertension will be analyzed in those patients who met any response criterion for hypertension at Visit OL22.
The primary efficacy endpoints will be assessed in the RW phase. The study will be considered to have a positive outcome if either of the 2 primary efficacy endpoints reaches statistical significance:
• In patients with DM/IGT, the mean change in AUCglucose from Visit OL22 to RW12/Early Termination (ET) in 2-hour oGTT glucose as compared between relacorilant and placebo arms
• 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
• In all patients, assessment of safety based on treatment-emergent adverse events (TEAEs) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
•AE: screening, baseline, every 4 weeks
•ABPM: screening, baseline, every 4 weeks from OL2
•oGTT: screening, baseline, every 4 weeks from OL6 |
|
| E.5.2 | Secondary end point(s) |
Other secondary efficacy endpoints are listed below by study phase (RW or OL), and the type of endpoint.
Secondary Efficacy Endpoints in the Randomized-Withdrawal Phase
Continuous Endpoints
• In patients with DM (HbA1c at Baseline ≥6.5%), the mean change
from Visit OL22 to RW12 in HbA1c, as compared between relacorilant
and placebo
• In patients with IGT at Baseline, the mean change from Visit OL22 to
RW12 in the 2-hour glucose value of the oGTT
• Mean change from Visit OL22 to RW12 in 24-hours average SBP as compared between
relacorilant and placebo
• Mean change from Visit OL22 to RW12 in 24-hours average DBP as compared between
relacorilant and placebo
• Mean change from Visit OL22 to RW12 in 24-hour average HR as compared between relacorilant and placebo (based on ABPM).
• Mean SBP, DBP, and HR at RW12 (end of dosing interval) as compared between relacorilant and placebo (based on ABPM).
• Mean difference in day and nighttime average SBP, DBP, and HR (based on ABPM) at RW12 as compared between relacorilant and placebo.
• Mean change from Visit OL22 to RW12 in body weight as compared
between relacorilant and placebo
• Mean change from Visit OL22 to RW12 in body fat measured with DXA
scan as compared between relacorilant and placebo
• Mean change from Visit OL22 to RW12 in Cushing Quality-of-Life (QoL)
score as compared between relacorilant and placebo
Endpoints Summarized with Proportions
• For patients in the DM/IGT subgroup, the proportion of patients with
any increase in dose of diabetes medication from Visit OL22 to RW12 as
compared between relacorilant and placebo.
• For patients in the DM/IGT subgroup, the proportion of patients who achieve 25% reduction in AUCglucose from Baseline OL to RW12 or achieve normalization of 2-hour oGTT as compared between relacorilant and placebo
• For patients in the hypertension subgroup, the proportion of patients
with any increase or modification in antihypertensive medication due to
worsening hypertension from Visit OL22 to RW12 as compared between
relacorilant and placebo
• Proportion of patients who worsened, as assessed by the Global
Clinical Response, from Visit OL22 to RW12 (i.e., a score of –1 at RW12
as compared with Visit OL22).
Secondary Efficacy Endpoints in the Open-Label Phase
Continuous Endpoints
• Mean change in Cushing Quality-of-Life (QoL) score from Baseline to
Visit OL22/ET
• In patients with IGT, the mean change in 2-hour oGTT glucose from
Baseline to Visit OL22/ET
• In patients with DM (HbA1c ≥6.5% at Baseline), the mean change in
HbA1c from Baseline to Visit OL22/ET
• In patients with DM/IGT, the mean change in AUCglucose from
Baseline to Visit OL22/ET.
• In patients with uncontrolled hypertension, the mean change in SBP
from Baseline to Visit OL22/ET
• In patients with uncontrolled hypertension, the mean change in DBP
from Baseline to Visit OL22/ET
• Mean change in body-fat composition from Baseline to Visit OL22/ET,
as determined by DXA
• Mean change in the Beck Depression Inventory®-II (BDI-II) score
from Baseline to Visit OL22/ET
• Mean change in body weight from Baseline to Visit OL22/ET
Endpoints Summarized with Proportions
• In patients with DM/IGT, the proportion of patients who meet any of the DM/IGT response criteria at Visit OL22/ET
• In patients with hypertension, the proportion of patients who meet any
of the hypertension response criteria at Visit OL22/ET
• In patients with IGT, the proportion of patients who achieved
normalization of glucose based on the 2-hour oGTT glucose and/or a
reduction in the 2-hour glucose by 50 mg/dL from Baseline to Visit
OL22/ET
• In patients with DM (HbA1c ≥6.5% at Baseline), the proportion of
patients with any decrease in dose of diabetes medication from Baseline
to Visit OL22/ET
• In patients with hypertension, the proportion of patients with
reduction or discontinuation of antihypertensive medications from
Baseline to Visit OL22/ET
• The proportion of patients with a positive Global Clinical Response
score at Visit OL22/ET. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Scr and/or Bln; then every 4wks: physical examination, body weight, waist circumference, vital signs, haematology, chemistry, pregnancy test
•Bln, every 4wks from OL6: sit-to-stand test, trail making test, Cushing QoL questionnaire, Beck Depression Inventory
•Scr, every 4wks OL6-OL14, OL22, RW12: UFC with creatinine, salivary cortisol
•Bln, OL22, RW12: Serum osteocalcin, thyroid function, lipid panel, sex hormone levels, DXA scan
•ECG: Scr, Bln, every 4wks OL2-OL14, OL22, RW12; follow-up
•Scr/Bln, every 4wks from OL6: ABPM; menstrual cycle information:
•HbA1c: Scr; Bln; OL10; OL22; RW12
•Pituitary MRI: Bln, OL22
•DST: Scr
•PK: OL18
•Photographs: Bln every 4wks during OL phase, RW12
•GR biomarkers: Scr, Bln, OL6, OL10, OL14, OL22, RW12
where:
Scr=Screening
Bln=Baseline |
|
| 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) |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Canada |
| Israel |
| United States |
| Austria |
| Poland |
| Bulgaria |
| Netherlands |
| Romania |
| Spain |
| Germany |
| Italy |
|
| 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
|
| The end of study is defined as the date of last contact (visit, telephone, e-mail) with any study patient. |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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