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    Summary
    EudraCT Number:2018-003096-35
    Sponsor's Protocol Code Number:CORT125134-455
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-01-27
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-003096-35
    A.3Full title of the trial
    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
    Antagonismo del recettore dei glucocorticoidi nel trattamento della sindrome di Cushing (GRACE): Studio di fase 3, in doppio cieco, controllato con placebo, con sospensione randomizzata sull’efficacia e la sicurezza di Relacorilant
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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.
    Uno studio per valutare se un prodotto chiamato relacorilant funziona ed è sicuro in pazienti affetti dalla sindrome di Cushing; alcuni pazienti riceveranno relacorilant, altri riceveranno un placebo.
    A.3.2Name or abbreviated title of the trial where available
    GRACE
    GRACE
    A.4.1Sponsor's protocol code numberCORT125134-455
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03697109
    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
    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 Address149 Commonwealth Drive
    B.5.3.2Town/ cityMenlo Park, California
    B.5.3.3Post code94025
    B.5.3.4CountryUnited States
    B.5.4Telephone number0016503273270
    B.5.5Fax number0016503273218
    B.5.6E-mailcorceptstudy455@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-4- YL)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 CodeSUB168996
    D.3.10 Strength
    D.3.10.1Concentration unit IU/mg international unit(s)/milligram
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    Endogenous Cushing syndrome
    Sindrome di Cushing endogena
    E.1.1.1Medical condition in easily understood language
    Cushing Syndrome caused by the body producing more cortisol than it needs
    Sindrome di Cushing causata da una produzione di cortisolo superiore al fabbisogno dell’organismo
    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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10011657
    E.1.2Term Cushings syndrome
    E.1.2System Organ Class 100000004860
    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 endogenous Cushing syndrome based on glycemic control and blood pressure (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
    • Valutare l’efficacia di relacorilant per il trattamento della sindrome di Cushing endogena, basata sul controllo glicemico e della pressione sanguigna (BP) alla Settimana 12 della fase di Sospensione randomizzata (RW) confrontata con il placebo
    • Valutare la sicurezza di relacorilant per il trattamento della sindrome di Cushing endogena
    E.2.2Secondary objectives of the trial
    • To assess changes in cortisol excess-related comorbidities (including diabetes mellitus/ impaired glucose tolerance [DM/IGT], 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
    • Valutare i cambiamenti nelle co-morbilità correlate all’eccesso di cortisolo (compreso diabete mellito/ compromissione della tolleranza al glucosio [DM/IGT], ipertensione, qualità della vita, peso corporeo e Risposta clinica globale) in pazienti con sindrome di Cushing endogena trattati con relacorilant nelle fasi in aperto (OL) e RW
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To enroll in the study, each patient must meet the following 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 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 > and =126 mg/dL and/or 2-hour oGTT plasma glucose > and =200 mg/dL at 2 hours or HbA1c> and = 6.5%), or IGT (plasma glucose > and =140 mg/dL and <200 mg/dL on a 2-hour oGTT)
    • Uncontrolled hypertension (mean SBP > and =135 to < and =170 mm Hg and/or mean DBP > and =85 to < and =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
    Per essere arruolati nello studio, ciascun/a paziente deve soddisfare i seguenti criteri di inclusione:
    1. Soggetti di sesso maschile o femminile di età compresa tra 18 e 80 anni inclusi
    2. Diagnosi biochimica confermata di sindrome di Cushing endogena in base alla presenza di almeno 2 dei seguenti parametri (Nieman et al. 2008):
    • UFC > limite superiore della norma (ULN) in almeno 2 test completi a 24 ore entro 4 settimane prima del Basale
    • Cortisolo salivare notturno >ULN in almeno 2 test (usando una provetta salivette) entro 4 settimane prima del Basale (Nota: il test non è appropriato per lavoratori che fanno il turno di notte e non può essere utilizzato per valutare l’idoneità)
    • Mancanza di soppressione del cortisolo (>1,8 µg/dL di cortisolo sierico) dopo test di soppressione con desametasone 1-mg nel per una notte o 2-mg in 48 ore durante lo Screening o entro 12 settimane prima di firmare il consenso informato
    3. Ha almeno 2 dei seguenti segni e sintomi clinici della sindrome di Cushing:
    • Caratteristiche corporee dell’apparenza cushoide (ad es. arrossamento del viso, facies a luna, deposito di grasso dorsocervicale, deposito di grasso sopraclavicolare)
    • Aumento del peso corporeo o obesità centrale
    • Debolezza muscolare prossimale
    • Bassa densità ossea misurata con scansione DEXA
    • Sintomi psichiatrici (compresa depressione o psicosi)
    • Manifestazioni cutanee: strie violacee, acne e/o irsutismo
    • Facilità di formazione di ecchimosi
    4. Ha almeno 1 dei seguenti parametri al Basale:
    • DM (glucosio plasmatico a digiuno =126 mg/dL e/o oGTT plasmatico a 2 ore =200 mg/dL a 2 ore), o HbA1c =6,5%), o IGT (glucosio plasmatico =140 mg/dL e <200 mg/dL all’oGTT a 2 ore) (American Diabetes Association 2018)
    • Ipertensione incontrollata (SBP media da =135 a =170 mm Hg e/o DBP media da =85 a =110 mm Hg) in base a ABPM a 24 ore (Parati et al. 2014)
    5. Se riceve trattamento medico per DM/IGT o ipertensione, non vi sono aumenti nella dose di medicinale da almeno 4 settimane prima della valutazione Basale
    6. Se riceve trattamento medico per la depressione, non vi sono aumenti della dose di medicinale da almeno 6 settimane prima del Basale
    7. Per le donne in età fertile, ha una test di gravidanza sierico negativo allo Screening e un test di gravidanza urinario negativo al Basale
    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 (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 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 < and =29 mL/min 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 (> and =120 ms)
    8. Has received pituitary radiation therapy for a Cushing syndrome-related tumor within 18 months of Screening
    9. Has used or plans to use any of the following treatments for Cushing syndrome within 4 weeks prior to Baseline:
    • Mifepristone
    • Adrenostatic medications: metyrapone, 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
    10. Has used or plans to use somatostatin receptor ligands: long-acting octreotide or pasireotide within 8 weeks prior to Baseline
    11. Has adrenocortical carcinoma
    12. Has used, or plans to use, mitotane within 3 months prior to Baseline.
    13. Has ectopic Cushing syndrome and a life expectancy of <3 years
    14. 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
    15. 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
    16. 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
    17. Ongoing use of any strong CYP3A4 inhibitor/inducer or any other prohibited medications
    18. Is pregnant or lactating
    19.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
    20. Has an acute or unstable medical problem that could be aggravated by treatment with the investigational study drug
    21. 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
    22. In the Investigator’s opinion, should not participate in the study or may not be capable of following the study schedule
    23. Has known HIV or hepatitis B or C infection
    24. Is a family member of one of the Sponsor’s employees, the Investigator, or the site staff directly working on the study
    I pazienti che soddisfano uno qualsiasi dei criteri elencati di seguito non potranno partecipare allo studio:
    1. Ipertensione incontrollata grave (SBP media >170 mm Hg o DBP media da >110 mm Hg allo Screening) in base a ABPM a 24 ore
    2. Ha DM scarsamente controllato (HbA1c >12% allo Screening)
    3. Ha un’anamnesi a “lungo termine” nota di ipertensione e diabete (definiti come ipertensione e diabete diagnosticati >10 anni prima della diagnosi iniziale di CS endogena)
    4. Ha risultati degli esami del fegato anormali (bilirubina totale >1,5×ULN o alanina aminotransferasi o aspartato aminotransferasi elevata >3×ULN al Basale)
    5. Ha grave insufficienza renale (tasso di filtrazione glomerulare =29 mL/min al Basale)
    6. Ha ipotiroidismo o ipertiroidismo clinicamente significativo, non controllato
    7. Ha un intervallo QT prolungato corretto per frequenza cardiaca usando l’equazione di Fridericia (QTcF) (>450 ms per gli uomini e >470 ms per le donne) con intervallo QRS normale (<120 ms) o intervallo QTcF >500 ms con intervallo QRS ampio (=120 ms)
    8. Ha ricevuto la radioterapia all’ipofisi per un tumore correlato alla sindrome di Cushing entro 18 mesi dallo Screening
    9. Ha usato o prevede di usare uno dei seguenti trattamenti per la sindrome di Cushing entro 4 settimane prima del Basale:
    • Mifepristone
    • Medicinali adrenostatici: metirapone, ketoconazolo, fluconazolo, aminoglutetimide, o etomidate
    • Antagonisti della serotonina: ciproeptadina, ketanserina, or ritanserina
    • Agonisti della dopamina: bromocriptina o cabergolina
    • Agonisti dell’acido aminobutirico: sodio valproato
    • Analoghi della somatostatina ad azione rapida: octreotide, lanreotide, or pasireotide
    10. Ha usato o prevede di usare ligandi del recettore della somatostatina: octreotide o pasireotide ad azione prolungata entro 8 settimane prima del Basale
    11. Ha un carcinoma adrenocorticale
    12. Ha usato o prevede di usare mitotano entro 3 mesi prima del Basale
    13. Ha la sindrome di Cushing ectopica e una aspettativa di vita <3 anni
    14. Ha la sindrome di pseudo-Cushing. I pazienti con sindrome di pseudo-Cushing nota o sospetta, in base all’anamnesi clinica (come pazienti con obesità grave, depressione maggiore, o storia di alcolismo) devono sottoporsi al test di stimolazione CRH/DDAVP con desametasone per escludere questa possibilità
    15. Ha assunto un farmaco sperimentale entro 4 settimane prima del Basale, o entro meno di 5 volte l’emivita del farmaco, a seconda del periodo che è più lungo
    16. Uso di medicinali antidiabetici, antiipertensivi, antidepressivi o ipolipidemizzanti che siano altamente dipendenti da CYP3A per la clearance e che non possano essere sottoposti a una modificazione della dose se co-somministrati con forti inibitori del CYP3A
    17. Uso corrente di qualsiasi forte inibitore/induttore del CYP3A4 o qualsiasi altro medicinale proibito
    18. È in stato di gravidanza o sta allattando con latte materno
    19. È una paziente di sesso femminile in età fertile (incluse tutte le donne di età <50anni, donne la cui sterilizzazione chirurgica è stata eseguita <6 mesi prima e donne che hanno avuto una mestruazione negli ultimi 2 anni) che non può utilizzare un metodo di contraccezione altamente efficace
    20. Ha un problema medico acuto o instabile che potrebbe peggiorare con il trattamento con il farmaco sperimentale in studio
    21. Ha un’anamnesi di ipersensibilità o reazione grave al farmaco in studio, a una classe simile di farmaci o all’eccipiente del farmaco in studio
    22. A parere del medico, non deve partecipare allo studio o può non essere in grado di seguire il programma dello studio
    23. Ha un’infezione nota all’HIV o epatite B o C
    24. È un familiare di uno dei dipendenti dello Sponsor, dello Sperimentatore o del personale del centro che lavora direttamente allo studio
    E.5 End points
    E.5.1Primary 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 > and =5 mm Hg
    – In patients who met only the DBP response criterion, an increase in DBP by > and =5 mm Hg
    – In patients who met both the SBP and DPB response criteria, an increase in either SBP or DBP by > and =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)
    Gli endpoint per le fasi OL e RW sono elencati di seguito. Nella fase RW, (1) gli endpoint correlati a DM/IGT saranno analizzati in quei pazienti che soddisfano un qualsiasi criterio di risposta per DM/IGT alla Visita OL22, e (2) gli endpoint correlati all’ipertensione saranno analizzati in quei pazienti che soddisfano un qualsiasi criterio di risposta per l’ipertensione alla Visita OL22.
    Endpoint primari
    • In pazienti con DM/IGT, il cambiamento medio nell’AUCglucosio dalla Visita OL22 a RW12 confrontato tra i bracci relacorilant e placebo
    • Nei pazienti con ipertensione, la proporzione di pazienti con una perdita di risposta rispetto all’ipertensione dalla Visita OL22 alla RW12 in base all’ABPM nelle 24 ore confrontata tra i bracci relacorilant e placebo, in cui la perdita di risposta viene definita come segue:
    – Nei pazienti che soddisfano solo il criterio SBP di risposta, un aumento di SBP > e =5 mm Hg
    – Nei pazienti che soddisfano solo il criterio DBP di risposta, un aumento di DBP > e =5 mm Hg
    – Nei pazienti che soddisfano sia il criterio SBP che DBP di risposta, un aumento di SBP o DBP > e =5 mm Hg
    – Qualsiasi aumento o modifica nel medicinale antiipertensivo dovuto al peggioramento dell’ipertensione
    • In tutti i pazienti, valutazione di sicurezza basata sugli eventi avversi dovuti al trattamento (TEAE)
    E.5.1.1Timepoint(s) of evaluation of this end point
    •AE: screening, baseline, every 4 weeks
    •ABPM: screening, every 4 weeks
    •oGTT: screening, every 4 weeks from OL6
    •AE: screening, basale, ogni 4 settimane
    •ABPM: screening, ogni 4 settimane
    •oGTT: screening, ogni 4 settimane da OL6
    E.5.2Secondary 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 RW 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 SBP as compared between relacorilant and placebo
    • Mean change from Visit OL22 to RW12 in DBP 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 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
    Secondary Efficacy Endpoints in the OL 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 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.
    Altri endpoint secondari di efficacia sono elencati di seguito per fase di studio (RW o OL) e il tipo di endpoint.
    Endpoint di efficacia secondari nella fase RW
    Endpoint continui
    • In pazienti con DM (HbA1c al Basale =6,5%), il cambiamento medio dalla Visita OL22 a RW12 in HbA1c confrontato tra relacorilant e placebo
    • In pazienti con IGT al Basale, il cambiamento medio dalla Visita OL22 a RW12 nel valore di glucosio dell’oGTT nelle 2 ore
    • Cambiamento medio dalla Visita OL22 a RW12 in SBP confrontato tra relacorilant e placebo
    • Cambiamento medio dalla Visita OL22 a RW12 in DBP confrontato tra relacorilant e placebo
    • Cambiamento medio dalla Visita OL22 a RW12 nel peso corporeo confrontato tra relacorilant e placebo
    • Cambiamento medio dalla Visita OL22 a RW12 nel grasso corporeo misurato mediante scansione DXA confrontato tra relacorilant e placebo
    • Cambiamento medio dalla Visita OL22 a RW12 nel punteggio della Qualità della vita (QoL) con Cushing confrontato tra relacorilant e placebo
    Endpoint riassunti con le proporzioni
    • Per i pazienti nel sottogruppo DM/IGT, la proporzione di pazienti con qualsiasi incremento della dose di medicinale per il diabete dalla Visita OL22 alla RW12 confrontato tra relacorilant e placebo
    • Per i pazienti nel sottogruppo ipertensione, la proporzione di pazienti con qualsiasi incremento o modifica di medicinale per l’ipertensione dovuto a peggioramento della stessa, dalla Visita OL22 alla RW12 confrontato tra relacorilant e placebo
    • Proporzione di pazienti che mostrano un peggioramento, valutato dalla Risposta clinica globale, dalla Visita OL22 alla RW12
    Endpoint secondari di efficacia nella fase OL
    Endpoint continui
    • Cambiamento medio del punteggio Qualità della vita (QoL) Cushing dal Basale alla Visita OL22/ET
    • In pazienti con IGT, il cambiamento medio nell’oGTT a 2 ore dal Basale alla Visita OL22/ET
    • In pazienti con DM (HbA1c =6,5%) al Basale, il cambiamento medio in HbA1c dal Basale alla Visita OL22/ET
    • In pazienti con ipertensione non controllata, il cambiamento medio nella SBP dal Basale alla Visita OL22/ET
    • In pazienti con ipertensione non controllata, il cambiamento medio nella DBP dal Basale alla Visita OL22/ET
    • Cambiamento medio nella composizione del grasso corporeo dal Basale alla Visita OL22/ET determinato mediante DXA
    • Cambiamento medio nel punteggio Beck Depression Inventory®-II (BDI-II) dal Basale alla Visita OL22/ET
    • Cambiamento medio del peso corporeo dal Basale alla Visita OL22/ET
    Endpoint riassunti con le proporzioni
    • In pazienti con DM/IGT, la proporzione di pazienti che soddisfa uno qualsiasi dei criteri di risposta DM/IGT alla Visita OL22/ET.
    • In pazienti con ipertensione, la proporzione di pazienti che soddisfa uno qualsiasi dei criteri di risposta dell’ipertensione alla Visita OL22/ET.
    • In pazienti con IGT, la proporzione di pazienti che ha raggiunto una normalizzazione del glucosio basata sull’oGTT a 2 ore e/o una riduzione del glucosio a 2 ore di 50 mg/dL dal Basale alla Visita OL22/ET
    • In pazienti con DM (HbA1c =6,5%) al Basale, la proporzione di pazienti con qualsiasi diminuzione di dose nel medicinale per il diabete dal Basale alla Visita OL22/ET
    • Nei pazienti con ipertensione, la proporzione di pazienti con una riduzione o interruzione del medicinale antiipertensivo dal Basale alla Visita OL22/ET
    • Proporzione di pazienti con un punteggio positivo di Risposta clinica globale alla Visita OL22/ET
    E.5.2.1Timepoint(s) of evaluation of this end point
    •Screening and/or baseline; then every 4wks: Physical examination, Body weight, Waist circumference, Vital signs; menstrual cycle information, sit-to-stand test, trail making test, Cushing QoL questionnaire, Beck Depression Inventory, Pregnancy test, haematology, chemistry
    •Screening, every 4wks from OL6: HbA1c; ABPM
    •Screening, every 4wks from OL6-OL14, OL22, RW12: UFC with creatinine, salivary cortisol
    •Baseline, OL22, RW12: Serum osteocalcin, thyroid function, lipid panel, sex hormone levels, DXA scan
    •ECG: screening, baseline, every 4wks OL2 to OL14, then at OL22, RW12 and at follow-up
    •Pituitary MRI: Baseline, OL22
    •DST: screening
    •PK: OL18
    •Photographs: Baseline, every 4wks during OL phase, RW12
    •GR biomarkers: Screening, Baseline, OL6, OL10, OL14, OL22, RW12
    •Screening e/o basale;dopo ogni 4 settimane: esame obiettivo,peso corporeo,circonferenza vita,parametri vitali; informazioni sul ciclo mestruale,sit-to-stand test,trail making test,QoL Cushing, Beck Depression Inventory,test di gravidanza, esami ematologici, esami chimici •Screening, ogni 4 settimane da OL6: HbA1c; ABPM •Screening, ogni 4 settimane da OL6-OL14, OL22, RW12: UFC con creatinina,cortisolo salivare •Basale,OL22, RW12:Osteocalcina sierica funzione tiroidea,quadro lipidico, livelli degli ormoni sessuali,scansione DXA •ECG: screening,basale, ogni 4 settimane da OL2 a OL14, successivamente a OL22,RW12 e follow-up •RM dell’ipofisi:Basale,OL22 •DST: screening •PK:OL10,OL14,OL18 •Fotografie:Basale,ogni 4 settimane durante la fase OL,RW12 •Biomarcatori GR:Basale,OL6,OL10,OL14,OL22,RW12
    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 Yes
    E.8.1.7.1Other trial design description
    fase di incremento della dose in aperto (22-26 settimane) e poi fase di sospensione randomizzata in
    open-label dose-escalation phase (22-26 weeks) then a doubleblind randomised withdrawal phase (12 we
    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 concerned8
    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 Information not present in EudraCT
    E.8.6.3If 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
    Bulgaria
    Germany
    Italy
    Netherlands
    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 any study patient.
    Per fine dello studio s’intende la data dell’ultimo contatto (visita, telefono, e-mail) con qualsiasi paziente dello studio.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days0
    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: 130
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 76
    F.4.2.2In the whole clinical trial 145
    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 meet the criteria defined in the Protocol will be permitted to continue relacorilant treatment in an extension study
    I pazienti che soddisfano i criteri definiti nel Protocollo (vedere la Sezione 3.1 Continuazione del trattamento) saranno autorizzati a proseguire il trattamento con relacorilant in uno studio di estensione.
    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 Decision2019-02-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2024-01-31
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