Primary • 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…
ID
Source
Brief title
Condition
- Adrenal gland disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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 or safety based on treatment-emergent adverse
events (TEAEs)
Secondary outcome
Please refer to protocol Am 5 05April 2023, section 3 Study Design: 3.6.2
Secondary Efficacy Endpoints. Other secondary efficacy endpoints are listed by
study phase (RW or OL), and by the type of endpoint.
Background summary
Endogenous Cushing syndrome is a rare multisystem disorder that results from
overproduction of the glucocorticoid hormone cortisol. In both adults and
children, Cushing syndrome is most commonly caused by adrenocorticotropic
hormone (ACTH) secretion pituitary tumor (Cushing disease). Other forms of
Cushing syndrome result from autonomous production or cortisol from adrenal
cortical tumors or overproduction or ACTH from non-pituitary tumors (ectopic
ACTH syndrome). The only curative treatment is resection of the tumor cause of
the excess cortisol. Depending on the nature of the underlying tumor (ie,
benign versus malignant, localized versus metastatic), the selected treatment,
radiotherapy, medical therapy, or a combination of these. Pharmacological
treatment serves to control the disease after unsuccessful surgery or
recurrence (Nieman et al. 2015). It may also be used to lower cortisol activity
to improve a patient*s condition prior to surgery and is employed as interim
therapy under specific circumstances, such as in patients waiting for
radiotherapy to be effective (Cuevas-Ramos 2014). Currently, there are four
United States (US) Food and Drug Administration (FDA) -approved medical
therapies for endogenous Cushing syndrome. The first, mifepristone (Korlym®),
was approved for the control of diabetes mellitus / impaired glucose tolerance
(DM / IGT) secondary to hypercortisolism in adult patients with endogenous
Cushing syndrome who have DM / IGT and have failed surgery or are not
candidates for surgery. The second, pasireotide (Signifor®), is a somatostatin
receptor agonist approved for the treatment of adult patients with Cushing
disease for whom pituitary surgery is not an option or has not been curative.
The third, osilodrostat (Isturisa®) is a cortisol-synthesis inhibitor approved
for the treatment of adult patients with Cushing*s disease for whom pituitary
surgery is not an option or has not been curative. Relacorilant (CORT125134) is
a potent, selective glucocorticoid receptor (GR) antagonist being developed for
the treatment of Cushing syndrome. Relacorilant is a high-affinity antagonist
of the GR (inhibition constant <1nM in a human GR binding assay and <10nM in a
human functional assay). Although the mechanism of action of relacorilant is
similar to that of mifepristone, relacorilant does not bind to the progesterone
receptor (PR). Given its selective and potent GR antagonism, relacorilant has
the potential advantage compared with mifepristone or not having any
antiprogesterone effects, including endometrial hypertrophy and the potential
for irregular vaginal bleeding.
Study objective
Primary
• 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
Secondary
• 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
Study design
This is a Phase 3, double-blind, placebo-controlled, RW study to assess the
efficacy, safety, and PK of relacorilant in patients with endogenous Cushing
syndrome and concurrent DM / IGT and / or uncontrolled hypertension.
Intervention
Please refer to the protocol section 5 Study Treatments and Management
Study burden and risks
Glucocorticoid receptor antagonism is a proven mechanism of action for the
treatment of DM / IGT secondary to hypercortisolism in adult patients with
Cushing syndrome (Fleseriu et al.2012). Because the mechanism of action of
relacorilant is similar to that of mifepristone, with the exception that it
does not bind the PR, relacorilant is expected to effectively treat Cushing
syndrome, but without the drawbacks or progesterone receptor antagonism that
may result in untoward reproductive effects and / or interruption of therapy.
In the Phase 2 study (Study CORT125134-451) in patients with endogenous Cushing
syndrome, relacorilant showed evidence of clinical benefit based on improvement
of cortisol-excess-related comorbidities. The drug was generally
well-tolerated, with the upper bound on dosing being typically musculoskeletal
complaints, a tolerability issue that patients can report.
Compared with the predecessor drug mifepristone, relacorilant offers two key
safety advantages: lack of affinity for the PR, and lack of significant
cortisol rise (a driver of hypokalemia in the marketed GR antagonist
mifepristone).
Based on the mechanism of action of relacorilant, there is a theoretical risk
of excessive GR antagonism, which could manifest by weakness, tiredness,
dizziness, hypoglycemia, dehydration, weight loss, nausea, vomiting, diarrhea,
and muscle aches. Since relacorilant does not affect the mineralocorticoid
receptor, it is unlikely that hypotension would occur in the absence of
antihypertensive medication. Because plasma glucocorticoid levels are not
decreased with relacorilant administration, a biochemical diagnosis or
excessive GR antagonism is not possible; diagnosis must rely on clinical
assessment. In cases of suspected excess GR antagonism, study drug will be
interrupted for 3 days and supplemental glucocorticoid will be given in high
doses to overcome the GR antagonism.
The safety profile of relacorilant in study patients will be monitored by AEs,
physical examinations, measurement of vital signs, 12-lead electrocardiograms
(ECGs), and blood tests for clinical chemistry and hematology parameters.
Patients meeting response criteria will be randomized 1: 1 to continue
relacorilant or receive a placebo equivalent (ie, have relacorilant withdrawn).
Patients proceeding into the RW phase will be at risk for relapse of symptoms
of Cushing syndrome, including worsening of diabetes, hypertension, and weight
gain.
In vitro data indicate that relacorilant is metabolized by multiple CYP enzymes
(CYP3A4, CYP2C8, and CYP3A5) and by carbonyl reductases. Data also indicate the
potential for relacorilant to perpetuate drug-drug interactions via inhibition
or CYP3A and transporter pathways. Patients taking any prohibited medication
are excluded from this study (refer to section 5.4 of protocol). If a
concomitant medication is required to treat an AE, in selecting the appropriate
concomitant medication, the Investigator must consider the risk of drug-drug
interaction. The Medical Monitor must approve all concomitant medications
required to treat an AE if there is a potential for drug-drug interaction. If
necessary, the patient will be withdrawn from the study.
Study procedures include venous blood sampling and noninvasive procedures,
including ECG recording, imaging, and vital-sign measurement. During
cannulation, more than 1 attempt may be needed to insert the cannula in a vein
or a patient and it is possible that bruising and / or inflammation may be
experienced at the site of cannulation. The total volume of blood collected
will not exceed 850 ml, unless the Investigator or designee considers
additional unplanned collection (s) are required for safety laboratory tests.
More information on the risks and benefits of relacorilant is provided in the
Investigator's Brochure.
Commonwealth Drive 149
Menlo Park CA 94025
US
Commonwealth Drive 149
Menlo Park CA 94025
US
Listed location countries
Age
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) (American Diabetes Association 2020) • 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
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 mm Hg 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 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-CRH
DDAVP stimulation test (Yanovski et al.1993, Giraldi et al. 2007, Yanovski et
al. 1998) 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 inducer or any other prohibited medications (Section
5.4.4) 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 (Section 4.6.2) 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-003096-35-NL |
| ClinicalTrials.gov | NCT03697109 |
| CCMO | NL68116.078.18 |