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    Summary
    EudraCT Number:2019-004956-12
    Sponsor's Protocol Code Number:CORT125134-456
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-07-10
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2019-004956-12
    A.3Full title of the trial
    Glucocorticoid Receptor Antagonism in the Treatment of Hypercortisolism in Patients with Cortisol-Secreting Adrenal Adenomas or Hyperplasia (GRADIENT): A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of Relacorilant
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to assess whether relacorilant works and is safe to use in patients with Hypercortisolism due to Cortisol-Secreting Adrenal Adenomas or Hyperplasia; some patients will receive relacorilant whilst others receive a placebo.
    A.3.2Name or abbreviated title of the trial where available
    GRADIENT
    A.4.1Sponsor's protocol code numberCORT125134-456
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04308590
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCorcept Therapeutics Incorporated
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCorcept Therapeutics Incorporated
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCorcept Therapeutics Incorporated
    B.5.2Functional name of contact pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street Address101 Redwood Shores Parkway
    B.5.3.2Town/ cityRedwood City, California
    B.5.3.3Post code94065
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 650 327-3270
    B.5.6E-mailGRADIENTstudy@corcept.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRelacorilant
    D.3.2Product code CORT125134
    D.3.4Pharmaceutical form Capsule, soft
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRelacorilant
    D.3.9.1CAS number 1496510-51-0
    D.3.9.2Current sponsor codeCORT125134
    D.3.9.3Other 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-4AYL)(4-(TRIFLUOROMETHYL)PYRIDIN-2-YL)METHANONE
    D.3.9.4EV Substance CodeSUB194345
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, soft
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hypercortisolism
    E.1.1.1Medical condition in easily understood language
    Hypercortisolism caused by the body producing more cortisol than it needs due to Cortisol-Secreting Adrenal Adenomas or Hyperplasia
    E.1.1.2Therapeutic area Body processes [G] - Physiological processes [G07]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.1
    E.1.2Level LLT
    E.1.2Classification code 10020611
    E.1.2Term Hypercortisolism
    E.1.2System Organ Class 10014698 - Endocrine disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To assess the efficacy of relacorilant for the treatment of hypercortisolism in patients with cortisol-secreting adrenal adenomas or hyperplasia, based on blood pressure (BP) control at Week 22 compared with placebo
    • To assess the safety of relacorilant for the treatment of hypercortisolism
    E.2.2Secondary objectives of the trial
    • To assess changes in the cortisol excess-related comorbidities (e.g.,body weight and glycemic control) in patients with hypercortisolism due to cortisol-secreting adrenal adenomas/hyperplasia
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To enroll in this study, each patient must meet the following key inclusion criteria:
    1. Male or female, 18 to 80 years of age, inclusive.
    2. Lack of cortisol suppression (>1.8 μg/dL serum cortisol with adequate dexamethasone levels) on either 1-mg overnight or 2-mg 48-hour DST during Screening.
    3. Suppressed or low (≤15 pg/mL) early-morning ACTH levels on at least 2 occasions during Screening.
    4. A radiologically confirmed benign adrenal lesion (single adenoma, multiple adenomas, hyperplasia [≥3 times the size of the normal adrenal gland]) within 3 years prior to Screening.
    5. 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).
    • Systolic hypertension (average SBP ≥130 to ≤170 mm Hg) based on 24-hour ABPM.
    6. 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.
    7. For women of childbearing potential, has a negative serum pregnancy test at Screening and negative urine pregnancy test at Baseline.
    E.4Principal exclusion criteria
    Patients who meet any of the following criteria will not be permitted entry to the study:
    1. Has severe, uncontrolled hypertension (average SBP >170 mm Hg or average DBP >110 mm Hg at Screening), based on 24-hour ABPM.
    2. Has poorly controlled DM (HbA1c >12% at Screening).
    3. Has DM Type 1.
    4. Has abnormal liver test results (total bilirubin >1.5×ULN or elevated alanine aminotransferase or aspartate aminotransferase >3×ULN at Baseline).
    5. Has severe renal insufficiency (glomerular filtration rate ≤29 mL/min/1.73 m2 at Baseline).
    6. Has uncontrolled, clinically significant hypothyroidism or hyperthyroidism.
    7. 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).
    8. Has persistent atrial fibrillation.
    9. Has used or plans to use any treatments for Cushing syndrome within 12 weeks prior to Screening and throughout the study, including mifepristone, metyrapone, osilodrostat, ketoconazole, fluconazole, or any investigational drug for treatment of Cushing syndrome
    10. Patients who require inhaled glucocorticoids and have no alternative
    option if their condition deteriorates during the study.
    11. Has adrenocortical carcinoma.
    12. 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 to rule-in or rule-out this possibility.
    13. Has a history of cyclic Cushing syndrome with fluctuating clinical
    manifestations.
    14. Has autonomous cosecretion of aldosterone.
    15. Has plans for adrenalectomy or nodulectomy during the study, including follow-up.
    16. Has taken any non-Cushing syndrome investigational drug within 4 weeks prior to Baseline, or within less than 5 times the drug’s half-life, whichever is longer.
    17. 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.
    18. Ongoing use of any strong CYP3A4 inducer or any other prohibited medications.
    19. Is pregnant or lactating.
    20. Is a female patient of childbearing potential who cannot use a highly effective method of contraception (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).
    21. Has an acute or unstable medical problem that could be aggravated by treatment with the investigational study drug.
    22. Has a history of severe reaction to the study drug, to a similar class of drug, or to the study drug’s excipient.
    23. In the Investigator’s opinion, should not participate in the study or may not be capable of following the study schedule.
    24. Has known HIV, hepatitis B, or hepatitis C infection and is taking medication for treatment of HIV, hepatitis B, or hepatitis C infection
    25. Has used mitotane prior to Baseline.
    E.5 End points
    E.5.1Primary end point(s)
    In patients with systolic hypertension, the mean change in 24-hour average systolic blood pressure (SBP) based on 24-hour ambulatory blood pressure monitoring (ABPM), from Baseline to Week 22 as compared between relacorilant and placebo arms.

    In all patients, assessment of safety based on treatment-emergent
    adverse events (TEAEs).
    E.5.1.1Timepoint(s) of evaluation of this end point
    • DM/IGT mean change in AUC glucose: from baseline to week 22 (every 4 weeks).
    •AE screening: every 4 weeks from week 2
    • ABPM (24-hour) test: Screening, every 4 weeks and at early termination
    E.5.2Secondary end point(s)
    Endpoints for Hypertension
    1. In patients with systolic hypertension at Baseline, mean change in average diastolic blood pressure (DBP) and HR (based on 24-hour ABPM).
    2. In patients with systolic hypertension at Baseline, mean change in daytime average SBP, DBP, and HR (based on 24-hour ABPM).
    3. In patients with systolic hypertension at Baseline, mean change in nighttime average SBP, DBP, and HR (based on 24-hour ABPM).
    4. In patients with systolic hypertension at Baseline, proportion of patients with any dose increase in antihypertensive medications due to
    worsening hypertension.
    5. In patients with systolic hypertension at Baseline, proportion of patients with a reduction in 24-hour average SBP by 5 mm Hg (based on
    24-hour ABPM).
    6. In patients with systolic hypertension at Baseline, proportion of patients with any dose decrease in antihypertensive medication due to
    improved blood pressure.
    7. In patients with systolic hypertension at Baseline, proportion of patients with normalization of the average SBP (<130 mm Hg, based on
    24-hour ABPM).
    Endpoints for Hyperglycemia
    1. In patients with DM/IGT, the mean change in AUC glucose, from Baseline to Week 22 as compared between relacorilant and placebo arms.
    2. In patients with DM (HbA1c at Baseline ≥6.5%), the mean change in HbA1c.
    3. In patients with DM/IGT (HbA1c at Baseline ≥5.7%), the mean change in HbA1c.
    4. Proportion of patients with HbA1c ≥6.5% at Baseline who achieved HbA1c <6.5%.
    5. In patients with DM at Baseline, proportion of patients who achieved 2-hour oGTT glucose <140 mg/dL.
    6. In patients with IGT at Baseline, proportion of patients who achieved 2-hour oGTT glucose <140 mg/dL.
    7. In patients with DM/IGT at Baseline, proportion of patients with any dose decrease of diabetes medication due to improved glucose control.
    8. In patients with DM/IGT at Baseline, proportion of patients with any dose increase of diabetes medications due to worsening hyperglycemia.
    9. In patients with DM/IGT in the ITT population, the proportion of patients who achieved decrease of AUCglucose of ≥25%, ≥10%, ≥5% and any decrease from Baseline to Week 22.
    10. In patients with DM/IGT in the ITT population, the mean change in 2-hour oGTT 2-hour timepoint from Baseline to Week 22.
    11. In patients with DM/IGT in the ITT population, the mean change in 2-hour oGTT predrink timepoint from Baseline to Week 22.
    Other Secondary Endpoint
    1. In all patients, the mean change in body weight and waist circumference.
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Physical examination, body weight, waist circumference, vital signs,
    hematology, chemistry, pregnancy test: Scr, Bln, Wk2, every 4wks from
    week2.
    • Sit-to-stand test, trail making test, Cushing QoL questionnaire, Beck
    Depression Inventory: Bln, every 4wks from week 6.
    • 2hr oGTT: Scr, Bln, every 4wks from week 2.
    • GR activity biomarkers test: Scr, wk6, 10, 14, 22 and ET
    • DXA scan: Bln, wk22 and ET
    • Dosing Dairy: Bln to wk 22
    where:
    Scr=Screening
    Bln=Baseline
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Israel
    United States
    Austria
    Bulgaria
    Germany
    Italy
    Poland
    Romania
    Spain
    E.8.7Trial 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 the last patient in the study.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days25
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days16
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state23
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 64
    F.4.2.2In the whole clinical trial 130
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients who complete the study will be permitted to continue relacorilant treatment in an extension study provided that they have at least 80% adherence with scheduled dosing (by capsule counts).
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-09-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-09-24
    P. End of Trial
    P.End of Trial StatusCompleted
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