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    Summary
    EudraCT Number:2016-000196-24
    Sponsor's Protocol Code Number:402-C-1504
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-06-01
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2016-000196-24
    A.3Full title of the trial
    A STUDY OF THE EFFICACY AND SAFETY OF BARDOXOLONE METHYL IN PATIENTS WITH CONNECTIVE TISSUE DISEASE-ASSOCIATED PULMONARY ARTERIAL HYPERTENSION
    Estudio de la eficacia y la seguridad de bardoxolona metilo en pacientes con hipertensión arterial pulmonar asociada a enfermedad del tejido conectivo
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A STUDY OF THE EFFICACY AND SAFETY OF BARDOXOLONE METHYL IN PATIENTS WITH CONNECTIVE TISSUE DISEASE-ASSOCIATED PULMONARY ARTERIAL HYPERTENSION
    Estudio de la eficacia y la seguridad de bardoxolona metilo en pacientes con hipertensión arterial pulmonar asociada a enfermedad del tejido conectivo
    A.3.2Name or abbreviated title of the trial where available
    CATALYST
    A.4.1Sponsor's protocol code number402-C-1504
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02657356
    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 SponsorReata Pharmaceuticals, Inc.
    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 supportReata Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationReata Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointClinical Study Manager
    B.5.3 Address:
    B.5.3.1Street Address2801 Gateway Drive, Suite 150
    B.5.3.2Town/ cityIrving
    B.5.3.3Post codeTX 75063
    B.5.3.4CountryUnited States
    B.5.4Telephone number900834223
    B.5.6E-mailRegistroEspanolDeEstudiosClinicos@druginfo.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 nameBardoxolone Methyl
    D.3.2Product code RTA 402
    D.3.4Pharmaceutical form Capsule, hard
    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 INNbardoxolone methyl
    D.3.9.1CAS number 218600-53-4
    D.3.9.2Current sponsor codeRTA 402
    D.3.9.3Other descriptive nameBARDOXOLONE METHYL, CDDO-Me, CDDO-Methyl Ester, NSC 713200, Chemical Name: Oleana-1,9(11)-dien-28-oic acid, 2-cyano-3,12-dioxo-, methyl ester
    D.3.9.4EV Substance CodeSUB33044
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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.IMP: 2
    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 nameBardoxolone Methyl
    D.3.2Product code RTA 402
    D.3.4Pharmaceutical form Capsule, hard
    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 INNbardoxolone methyl
    D.3.9.1CAS number 218600-53-4
    D.3.9.2Current sponsor codeRTA 402
    D.3.9.3Other descriptive nameBARDOXOLONE METHYL, CDDO-Me, CDDO-Methyl Ester, NSC 713200, Chemical Name: Oleana-1,9(11)-dien-28-oic acid, 2-cyano-3,12-dioxo-, methyl ester
    D.3.9.4EV Substance CodeSUB33044
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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
    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
    Connective Tissue Disease-Associated Pulmonary Arterial Hypertension (WHO Group I CTD-PAH)
    Hipertensión arterial pulmonar asociada a enfermedad del tejido conectivo (HAP-ETC del grupo I según la OMS)
    E.1.1.1Medical condition in easily understood language
    Connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH)
    Hipertensión arterial pulmonar asociada a enfermedad del tejido conectivo (HAP-ETC)
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    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 bardoxolone methyl relative to placebo.
    Evaluar la eficacia de bardoxolona metilo en comparación con un placebo
    E.2.2Secondary objectives of the trial
    To assess the safety of bardoxolone methyl relative to placebo
    Evaluar la seguridad de bardoxolona metilo en comparación con un placebo
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    a) Pulmonary Function Testing and Diffusion Capacity (DLco) assessments.
    b) Additional PK testing.

    The diffusion capacity (DLco) assessment will be performed on a subset of sites.
    Similarly, although systemic exposure to bardoxolone methyl will be assessed in all patients, there will be a subgroup of patients that will participate on a more extensive PK testing.

    Although the protocol refers to these as "substudies" separate sub-study protocols were not created to describe the procedures.
    Please refer to study protocol section 9.10.12. for details of the Pulmonary Function Testing and Diffusion Capacity (DLco) testing and section 9.10.31. for details regarding the optional PK sub-study.

    DLCO Substudy Objective: Evaluate the diffusion capacity for carbon monoxide in patients enrolled at sites that have the capability to perform this assessment and agree to participate in the substudy.

    PK Substudy Objective: Collect additional serial blood samples to obtain more robust pharmacokinetic parameter estimates in patients that agree to participate in the substudy.
    a) Evaluaciones de pruebas de función y capacidad de difusión pulmonar (DLco).
    b) Pruebas adicionales de FC.

    La evaluación de la capacidad de difusión (DLco) se llevará a cabo en un subgrupo de centros. Del mismo modo, aunque la exposición sistémica a bardoxolona metilo se evaluará en todos los pacientes, habrá un subgrupo de pacientes que participará en una prueba FC más extensa.

    A pesar de que el protocolo se refiere a éstos como "sub-estudios" no se han creado protocolos independientes para describir los procedimientos de los sub-estudios.
    Por favor refiérase a la sección 9.10.12. del protocolo del estudio para mayor información sobre las pruebas de función y de capacidad de difusión pulmonar, y a la sección 9.10.31. para una información más detallada sobre el sub-estudio opcional de FC.

    Objetivo del sub-estudio DLco: Evaluar la capacidad de difusión del monóxido de carbono en pacientes incluidos en centros que tengan capacidad para llevar a cabo esta evaluación y estén de acuerdo en participar en el sub-estudio.

    Objetivo del sub-estudio de FC: recoger muestras de sangre en serie adicionales para obtener estimaciones de los parámetros farmacocinéticos más robustas en los pacientes que estén de acuerdo en participar en el sub-estudio.
    E.3Principal inclusion criteria
    1. Adult male and female patients ≥ 18 to ≤ 75 years of age upon study consent;
    2. BMI > 18.5 kg/m2;
    3. Symptomatic pulmonary hypertension WHO/NYHA FC class II and III;
    4. WHO Group I PAH associated with connective tissue disease;
    5. Had a diagnostic right heart catheterization performed and documented within 36 months prior to Day 1 that confirmed a diagnosis of PAH according to all the following criteria:
    a. Mean pulmonary artery pressure ≥ 25 mm Hg (at rest);
    b. Pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg;
    c. Pulmonary vascular resistance > 240 dyn•sec/cm5 or > 3 mm Hg/liter (L)/minute;
    6. Has BNP level ≤ 400 pg/mL;
    7. Had an average 6MWD ≥ 150 meters on two consecutive tests performed on different days prior to randomization, with both tests measuring within 15% of one another;
    8. Has been receiving no more than two (2) approved disease-specific PAH therapies. PAH therapy must have been at a stable dose for at least 90 days prior to Day 1. No additions or changes should be made to PAH therapies and doses should remain stable for the duration of the study;
    9. Has maintained a stable dose for 30 days prior to Day 1 if receiving any of the following therapies that may affect PAH: vasodilators (including calcium channel blockers), digoxin, L-arginine supplementation, or oxygen supplementation. No additions or changes should be made to therapies and doses should remain stable for the duration of the study;
    10. If receiving treatment for CTD with prednisone or any other drugs, doses must remain stablefor at least 30 days prior to Day 1 and for the duration of the study;
    11. Had pulmonary function tests (PFTs) within 90 days prior to Day 1 with total lung capacity ≥ 65% (predicted);
    12. Had a ventilation-perfusion (V/Q) lung scan, spiral/helical/electron beam computed tomography (CT), or pulmonary angiogram prior to Day 1 that shows no evidence of thromboembolic disease (i.e., should note normal or low probability for pulmonary embolism). If V/Q scan was abnormal (i.e., results other than normal or low probability), then a confirmatory CT or selective pulmonary angiography must exclude chronic thromboembolic pulmonary hypertension;
    13. Has adequate kidney function defined as an estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2 as measured by the central lab;
    14. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures;
    15. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative) has been informed of all pertinent aspects of the study prior to initiation of any patient-mandated procedures.
    1. Pacientes adultos de ambos sexos, de 18 a 75 años de edad, que den su consentimiento para el estudio;
    2. IMC > 18,5 kg/m2;
    3. Hipertensión pulmonar sintomática de clase II y III según la CF de la OMS/NYHA;
    4. HAP de grupo 1 según la OMS asociada a enfermedad del tejido conectivo;
    5. Diagnóstico de cateterismo cardíaco derecho emitido y documentado en los 36 meses previos al día 1, que confirme un diagnóstico de HAP según los criterios siguientes:
    a. Presión media en la arteria pulmonar ≥ 25 mm Hg (en reposo);
    b. Presión de enclavamiento capilar pulmonar (PECP) ≤ 15 mm Hg;
    c. Resistencia vascular pulmonar > 240 dyn•s/cm5 o > 3 mm Hg/litro (l)/minuto;
    6. Nivel de BNP ≤ 400 pc/ml;
    7. Promedio de DR6M ≥ 150 metros en dos pruebas consecutivas efectuadas en días diferentes antes de la aleatorización y cuyos resultados no difieran en más del 15%;
    8. Haber recibido no más de dos (2) tratamientos aprobados específicos de la HAP. El tratamiento de la HAP debe haberse mantenido con una dosis estable desde al menos 90 días antes del día 1. No se permiten adiciones ni cambios en el tratamiento de la HAP, y las dosis deben mantenerse estables durante todo el periodo de estudio;
    9. Haber mantenido una dosis estable en los 30 días previos al día 1 en caso de recibir los siguientes tratamientos que influyen en la HAP: vasodilatores (incluidos antagonistas del calcio), digoxina, suplementos de L-arginina o suplemento de oxígeno. No se permiten adiciones ni cambios en los tratamientos, y las dosis deben mantenerse estables durante todo el periodo de estudio;
    10. Si se está tratando la ETC con prednisona u otros medicamentos, las dosis deben mantenerse estables en los 30 días previos al día 1 y durante todo el periodo de estudio;
    11. Haber realizado pruebas funcionales respiratorias (PFT) en los 90 días previos al día 1 con un resultado de capacidad pulmonar total ≥ 65% (predictivo);
    12. Haberse sometido antes del día 1 a una gammagrafía de ventilación/perfusión pulmonar (V/Q), una tomografía computarizada por haz electrónico espiral/helicoidal (TC) o una angiografía pulmonar que descarte signos de enfermedad tromboembólica (es decir, que indique probabilidad normal o baja de embolia pulmonar). Si el escáner de V/Q da un resultado anómalo (es decir, un resultado distinto de probabilidad normal o baja), habrá que practicar una angiografía pulmonar selectiva o TC de confirmación para descartar la hipertensión pulmonar tromboembólica crónica;
    13. Tener una función renal adecuada, que se define como una filtración glomerular estimada (FGe) ≥ 45 ml/min/1,73 m2 determinada en el laboratorio central;
    14. Capacidad y disposición para cumplir el calendario de visitas, el plan de tratamiento, las pruebas analíticas y otros procedimientos relacionados con el estudio;
    15. Existencia de un documento de consentimiento informado, firmado y fechado personalmente, que indique que se ha informado al paciente (o a su representante legal) de todos los aspectos pertinentes del estudio antes de iniciar cualquier procedimiento que involucre al paciente.
    E.4Principal exclusion criteria
    1. Participation in other investigational clinical studies involving interventional products being tested or used in a way different from the approved form or when used for an unapproved indication within 30 days prior to Day 1;
    2. Initiation of an exercise program for cardio-pulmonary rehabilitation within 90 days prior to Day 1 or planned initiation during the study;
    3. Stopped receiving any PAH chronic therapy within 60 days prior to Day 1;
    4. Received a dose of prednisone > 20 mg/day (or equivalent dose if other corticosteroid) within 30 days prior to Day 1;
    5. Received intravenous (iv) or subcutaneous (sc) prostacyclin/prostacyclin analogues within 90 days prior to Day 1;
    6. Received intravenous inotropes within 30 days prior to Day 1;
    7. Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 160 mm Hg or sitting diastolic BP > 100 mm Hg during Screening after a period of rest;
    8. Has systolic BP < 90 mm Hg during Screening after a period of rest;
    9. Has a history of clinically significant left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following: a. Congenital or acquired valvular disease if clinically significant apart from tricuspid valvular insufficiency due to pulmonary hypertension; b. Pericardial constriction; c. Restrictive or congestive cardiomyopathy; d. Left ventricular ejection fraction < 40% per echocardiogram (ECHO) within 90 days of Day 1; e. Symptomatic coronary artery disease within the last 3 years;
    10. Acutely decompensated heart failure within 30 days prior to Day 1, per investigator assessment;
    11. Has more than two of the following clinical risk factors for left ventricular diastolic dysfunction: a. Age > 65 years; b. BMI ≥ 30 kg/m2; c. History of systemic hypertension; d. History of type 2 diabetes; e. History of atrial fibrillation;
    12. History of atrial septostomy within 180 days prior to Day 1;
    13. History of uncontrolled obstructive sleep apnea;
    14. Has a history of portal hypertension or chronic liver disease, including hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication) defined as mild to severe hepatic impairment (Child-Pugh Class A-C);
    15. Serum aminotransferase (ALT or AST) levels > 1.5X the upper limit of normal (ULN) at Screening;
    16. Hemoglobin (Hgb) concentration < 8.5 g/dL at Screening;
    17. Diagnosis of Down syndrome;
    18. History of malignancy within 5 years prior to Screening, with the exception of localized skin or cervical carcinomas;
    19. Untreated or uncontrolled active bacterial, fungal, or viral infection;
    20. Known or suspected active drug or alcohol abuse, per investigator judgment;
    21. Use of Herbalife supplements within 14 days prior to Day 1;
    22. Use of inhaled nitric oxide within 7 days prior to Screening and Day 1 visits, excluding acute vasodilator testing during diagnostic cardiac catheterization;
    23. Major surgery within 30 days prior to Day 1 or planned to occur during the course of the study;
    24. Unwilling to practice acceptable methods of birth control (both males who have partners of childbearing potential and females of childbearing potential) during Screening, while taking study drug, and for at least 30 days after the last dose of study drug is ingested;
    25. Women who are pregnant or breastfeeding;
    26. Any disability or impairment that would prohibit performance of the 6MWT;
    27. Any abnormal laboratory level that, in the opinion of the investigator, would put the patient at risk by trial enrollment;
    28. Patient is, in the opinion of the investigator, unable to comply with the requirements of the study protocol or is unsuitable for the study for any reason;
    29. Known hypersensitivity to any component of the study drug;
    30. Unable to communicate or cooperate with the investigator because of language problems, poor mental development, or impaired cerebral function.
    1. Participación en otros estudios de investigación clínica con productos de intervención que se estén ensayando o usando de manera diferente a la aprobada, o para una indicación no autorizada, en los 30 días que preceden al día 1;
    2. Inicio de un programa de ejercicios de rehabilitación cardiopulmonar en los 90 días previos al día 1, o previsión de iniciarlo durante el estudio;
    3. Dejar de recibir cualquier tratamiento crónico de la HAP en los 60 días previos al día 1;
    4. Haber recibido una dosis de prednisona > 20 mg/día (o dosis equivalente de otro corticosteroide) en los 30 días previos al día 1;
    5. Haber recibido por vía intravenosa (IV) o subcutánea (SC) prostaciclina o análogos de la prostaciclina en los 90 días previos al día 1;
    6. Haber recibido fármacos inotrópicos intravenosos en los 30 días previos al día 1;
    7. Presentar hipertensión sistémica no controlada, demostrada por una presión arterial (PA) sistólica en sedestación > 160 mm Hg o una PA diastólica en sedestación > 100 mm Hg, después de un periodo de reposo, durante la selección;
    8. PA sistólica < 90 mm Hg, después de un periodo de reposo, durante la selección;
    9. Antecedentes de insuficiencia cardíaca izquierda clínicamente relevante y/o cardiopatía clínicamente relevante, que incluyen entre otros los siguientes:
    a. Valvulopatía congénita o adquirida si es clínicamente relevante, aparte de la insuficiencia de la válvula tricúspide debida a la hipertensión pulmonar;
    b. Constricción pericárdica;
    c. Miocardiopatía restrictiva o congestiva;
    d. Fracción de eyección del ventrículo izquierdo < 40% determinada mediante ecocardiografía en los 90 días previos al día 1;
    e. Arteriopatía coronaria sintomática en los 3 últimos años;
    10. Insuficiencia cardíaca aguda descompensada en los 30 días previos al día 1, según evaluación del investigador;
    11. Presenta más de dos de los siguientes factores de riesgo clínico de disfunción diastólica del ventrículo izquierdo:
    a. Edad > 65 años;
    b. IMC ≥ 30 kg/m2;
    c. Antecedentes de hipertensión sistémica;
    d. Antecedentes de diabetes de tipo 2;
    e. Antecedentes de fibrilación auricular;
    12. Antecedentes de septostomía auricular en los 180 días previos al día 1;
    13. Antecedentes de apnea obstructiva del sueño no controlada;
    14. Antecedentes de hipertensión portal o hepatopatía crónica, incluso hepatitis B y/o hepatitis C (con signos de infección reciente o de replicación viral activa), definida como insuficiencia hepática de moderada a grave (clase A-C de Child-Pugh);
    15. Niveles séricos de aminotransferasas (ALT o AST) > 1,5 veces el límite superior de la normalidad (SLN) en la selección;
    16. Concentración de hemoglobina (Hb) < 8,5 g/dl en la selección;
    17. Diagnóstico de síndrome de Down;
    18. Antecedentes de neoplasia maligna en los 5 años previos a la selección, salvo carcinoma cervical o de piel localizado;
    19. Infección activa por bacterias, hongos o virus no tratada o no controlada.
    20. Demostración o sospecha de alcoholismo o drogodependencia activa, a criterio del investigador;
    21. Uso de suplementos de herbolario en los 14 días previos al día 1;
    22. Uso de óxido nítrico inhalado en los 7 días previos a las visitas de selección y del día 1, salvo en los estudios de vasodilatación aguda durante la cateterización cardíaca con fines diagnósticos.
    23. Cirugía mayor en los 30 días previos al día 1, o programada para el periodo de duración del estudio;
    24. No aceptar la práctica de métodos anticonceptivos aceptables (mujeres en edad fértil y varones cuya pareja está en edad fértil) durante la selección, mientras se toma el fármaco del estudio y durante al menos 30 días después de recibir la última dosis del fármaco del estudio;
    25. Mujeres embarazadas o lactantes;
    26. Cualquier discapacidad o insuficiencia que impida realizar la prueba de la DR6M;
    27. Cualquier anomalía analítica que, a criterio del investigador, haga que la inclusión en el ensayo suponga un riesgo para el paciente;
    28. Incapacidad del paciente para, a criterio del investigador, cumplir los requisitos impuestos por el protocolo de estudio o someterse al estudio por cualquier motivo;
    29. Hipersensibilidad conocida a alguno de los componentes del fármaco del estudio;
    30. Incapacidad para comunicarse o colaborar con el investigador debido o problemas de lenguaje, desarrollo mental deficiente o trastornos de la función cerebral.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in six-minute-walk distance (6MWD) relative to placebo at week 24.
    Variación de la distancia recorrida en seis minutos (DR6M), en comparación con el placebo, en la semana 24
    E.5.1.1Timepoint(s) of evaluation of this end point
    Six minute walk test will be performed at screening, baseline, weeks 4, 8, 16, 24, End of treatment (if applicable) and Follow-up visit (week 28). Change from baseline will be calculated by comparing results at Day 1 and Week 24.
    Se llevará a cabo una prueba de marcha de seis minutos en la selección, visita basal, semanas 4, 8, 16, 24, final del tratamiento (si procede) y visita de seguimiento (semana 28). El cambio desde la visita basal se calculará mediante la comparación de resultados en el Día 1 y en la semana 24.
    E.5.2Secondary end point(s)
    SECONDARY ENDPOINTS
    Time-to-first clinical improvement event consisting of a persistent change for any of the following:
    • Improvement by at least one WHO functional class.
    • Increase from baseline in 6 minute walk distance (6MWD) by at least 10%.
    • Decrease from baseline in creatine kinase (as a surrogate biomarker for muscle injury and inflammation) by at least 10%.

    OTHER
    Exploratory Efficacy Endpoints:
    Time-to-first clinical worsening event consisting of any of the following:
    • Persistent worsening of WHO functional class due to worsening pulmonary hypertension
    • Initiation of parenteral prostacyclin therapy due to worsening pulmonary hypertension
    • Heart/lung transplantation or atrial septostomy
    • All cause death

    Safety Endpoints:
    Frequency, intensity, and relationship to study drug of adverse events and serious adverse events, and change from baseline in the following assessments: physical examinations, vital sign measurements, 12-lead electrocardiograms (ECGs), clinical laboratory measurements, and weight.

    Additional Exploratory Endpoints
    Change from baseline in the following assessments: parameters assessed with an optional wearable activity monitor; Borg dyspnea index at termination of 6MWT; WHO/NYHA functional class (FC); quality of life (SF-36); autoantibody levels; number of digital ulcers in scleroderma patients; and proportion of scleroderma patients with no new digital ulcers.

    Pharmacokinetic Endpoints:
    Systemic exposure to bardoxolone methyl will be assessed in all patients. Additional blood sampling will be performed in a subset of patients for the purpose of obtaining more robust pharmacokinetic (PK) parameter estimates (e.g., AUC, Cmax, Tmax) for bardoxolone methyl in the CTD-PAH population.
    CRITERIOS DE VALORACIÓN SECUNDARIOS:
    Tiempo hasta el primer acontecimiento de mejoría clínica, definido como un cambio persistente en cualquiera de los siguientes:
    - Mejoría en al menos una clase funcional de la OMS.
    - Aumento de la DR6M de al menos un 10% con respecto al valor inicial.
    - Disminución de la creatina quinasa (como biomarcador indirecto de la lesión e inflamación muscular) de al menos un 10% con respecto al valor inicial.

    OTROS
    Criterios de valoración de la eficacia exploratorios:
    Tiempo hasta el primer acontecimiento de empeoramiento clínico, definido como cualquiera de los siguientes:
    - Agravamiento persistente de la clase funcional de la OMS debido a un deterioro de la hipertensión pulmonar (definido como una reducción persistente de la DR6M en más del 15% del valor inicial).
    - Instauración de tratamiento parenteral con prostaciclina debido a un deterioro de la hipertensión pulmonar (definido como una reducción persistente de la DR6M en más del 15% del valor inicial)
    - Trasplante de corazón/pulmón o septostomía auricular.
    - Muerte por cualquier causa.

    Criterios de valoración de la seguridad:
    Frecuencia, intensidad y relación con el fármaco del estudio de los acontecimientos adversos y acontecimientos adversos graves, y variación respecto a los valores iniciales de los parámetros siguientes: exploraciones físicas, mediciones de las constantes vitales, electrocardiogramas (ECG) de 12 derivaciones, parámetros analíticos y peso.

    Criterios de valoración exploratorios adicionales:
    Variación respecto a los valores iniciales de los parámetros siguientes: parámetros valorados con un monitor de actividad portátil opcional; índice de disnea de Borg al finalizar la DR6M; clasificación funcional (CF) de la OMS/NYHA; cuestionario de calidad de vida (SF-36); niveles de autoanticuerpos; número de úlceras digitales en los pacientes con esclerodermia; y porcentaje de pacientes con esclerodermia que no presentan úlceras digitales nuevas.

    Criterios de valoración de Farmacocinética:
    La exposición sistémica a bardoxolona metilo se evaluará en todos los pacientes. Se llevarán a cabo muestras de sangre adicionales en un subgrupo de pacientes con el fin de obtener estimaciones más robustas de los parámetros farmacocinéticos (FC) (por ejemplo, AUC, Cmax, Tmax) para bardoxolona metilo en la población HAP-ETC .
    E.5.2.1Timepoint(s) of evaluation of this end point
    SECONDARY:
    Whenever clinical improvement is observed (time to improvement constitute the endpoint).
    Clinical exam and blood chemistry (including creatine kinase testing) will be performed at screening, baseline, weeks 1, 2, 4, 8, 16, 24, End of treatment (if applicable) and Follow-up visit (week 28).

    6 minute walk and assesment of dyspnea and fatigue will be performed at screening, baseline, weeks 4, 8, 16, 24, End of treatment (if applicable) and Follow-up visit (week 28).

    Other:
    Exploratory and Ancillary Study Measures and Time Points for Exploratory Efficacy, Safety, additional exploratory and Pharmacokinetics are detailed in the study protocol.
    SECUNDARIO:
    Cada vez que se observe una mejoría clínica (el tiempo para la mejoría constituye el criterio de valoración).
    Se llevará a cabo un examen clínico y bioquímico de la sangre (incluyendo pruebas de creatina quinasa) en la selección, la visita basal, las semanas 1, 2, 4, 8, 16, 24, final del tratamiento (si procede) y visita de seguimiento (semana 28).

    Se llevará a cabo una marcha de 6 minutos, y valoración de la disnea y la fatiga en la selección, la visita basal, las semanas 4, 8, 16, 24, final del tratamiento (si procede) y visita de seguimiento (semana 28).

    Otro:
    En el protocolo de estudio se detallan medidas exploratorias y del estudio auxiliar y puntos de tiempo para eficacia exploratoria, seguridad, exploratoria adicional y farmacocinética.
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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 Yes
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA24
    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
    Argentina
    Australia
    Belgium
    Brazil
    Canada
    Chile
    Czech Republic
    Germany
    Ireland
    Israel
    Japan
    Mexico
    Netherlands
    Spain
    United Kingdom
    United States
    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
    LVLS
    UVUP
    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 months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months3
    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: 117
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 13
    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 state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 44
    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)
    The Sponsor plans to execute an open-label extension study of patients that complete the base trial, are treatment-compliant and provide informed consent for this study. The protocol is not yet available; however, current expected design consider continuation of treatment until all patients are withdrawn from the trial (subject decision or medical reasons), lost to follow-up, die, or bardoxolone methyl becomes commercially available (whichever occurs first).
    El promotor planea llevar a cabo un estudio abierto de extensión para los pacientes que completen el ensayo base, cumplan con el tratamiento y den su consentimiento para este estudio. El protocolo no está disponible todavía pero el diseño esperado actual considera la continuación del tratamiento hasta que los pacientes se retiren del ensayo (por decisión propia o por razones médicas), pérdida de seguimiento, muerte o bardoxolona metilo esté disponible comercialmente (lo que ocurra primero).
    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 Decision2016-07-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-06-30
    P. End of Trial
    P.End of Trial StatusCompleted
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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