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    Summary
    EudraCT Number:2018-004039-64
    Sponsor's Protocol Code Number:MYK-461-007
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-09-02
    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 number2018-004039-64
    A.3Full title of the trial
    A Long-term Safety Extension Study of Mavacamten (MYK-461) in Adults with Hypertrophic Cardiomyopathy Who Have Completed the MAVERICK-HCM (MYK-461-006) or EXPLORER-HCM (MYK-461-005) Trials (MAVA-LTE)
    MAVA-LTE: Estudio de extensión de la seguridad a largo plazo de Mavacamten (MYK 461) en adultos con miocardiopatía hipertrófica que hayan completado los estudios MAVERICK-HCM (MYK-461-006) o EXPLORER-HCM (MYK 461 005)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Long-term Safety Extension Study of Mavacamten (MYK-461) in Adults with Hypertrophic Cardiomyopathy Who Have Completed the MAVERICK-HCM (MYK-461-006) or EXPLORER-HCM (MYK-461-005) Trials (MAVA-LTE)
    MAVA-LTE: Estudio de extensión de la seguridad a largo plazo de Mavacamten (MYK 461) en adultos con miocardiopatía hipertrófica que hayan completado los estudios MAVERICK-HCM (MYK-461-006) o EXPLORER-HCM (MYK 461 005)
    A.3.2Name or abbreviated title of the trial where available
    MAVA-LTE
    A.4.1Sponsor's protocol code numberMYK-461-007
    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 SponsorMyoKardia, 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 supportMyoKardia, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMyoKardia, Inc.
    B.5.2Functional name of contact pointClinical Trial or Medical Inquiries
    B.5.3 Address:
    B.5.3.1Street Address333 Allerton Avenue
    B.5.3.2Town/ citySouth San Francisco, CA
    B.5.3.3Post code94080
    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 nameMavacamten
    D.3.2Product code MYK-461
    D.3.4Pharmaceutical form Capsule
    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 INNNA
    D.3.9.1CAS number NA
    D.3.9.2Current sponsor codeMYK-461
    D.3.9.3Other descriptive nameMAVACAMTEN
    D.3.9.4EV Substance CodeSUB191202
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number15
    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 nameMavacamten
    D.3.2Product code MYK-461
    D.3.4Pharmaceutical form Capsule
    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 INNNA
    D.3.9.1CAS number NA
    D.3.9.2Current sponsor codeMYK-461
    D.3.9.3Other descriptive nameMAVACAMTEN
    D.3.9.4EV Substance CodeSUB191202
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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: 3
    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 nameMavacamten
    D.3.2Product code MYK-461
    D.3.4Pharmaceutical form Capsule
    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 INNNA
    D.3.9.1CAS number NA
    D.3.9.2Current sponsor codeMYK-461
    D.3.9.3Other descriptive nameMAVACAMTEN
    D.3.9.4EV Substance CodeSUB191202
    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.IMP: 4
    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 nameMavacamten
    D.3.2Product code MYK-461
    D.3.4Pharmaceutical form Capsule
    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 INNNA
    D.3.9.1CAS number NA
    D.3.9.2Current sponsor codeMYK-461
    D.3.9.3Other descriptive nameMAVACAMTEN
    D.3.9.4EV Substance CodeSUB191202
    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.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hypertrophic Cardiomyopathy
    Miocardiopatía hipertrófica
    E.1.1.1Medical condition in easily understood language
    Inherited heart disease causing thickening of the muscle wall of the heart
    Enfermedad cardíaca heredada que provoca el engrosamiento de las paredes musculares del corazón
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10020871
    E.1.2Term Hypertrophic cardiomyopathy
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To assess the long-term safety and tolerability of mavacamten in participants with HCM previously enrolled in 1 of 2 placebo-controlled trials: MAVERICK-HCM for nHCM and EXPLORER-HCM for oHCM.
    Evaluar la seguridad y la tolerabilidad a largo plazo de mavacamten en participantes con MCH previamente inscritos en uno de los dos ensayos controlados con placebo: MAVERICK-HCM para nMCH y EXPLORER-HCM para oMCH.
    E.2.2Secondary objectives of the trial
    • To assess in the MAVERICK-LTE and EXPLORER-LTE cohorts the long-term effects of mavacamten on symptoms and echocardiographic measures of cardiac function
    • To assess LVOT obstruction as determined by Doppler echocardiography in the EXPLORER-LTE cohort
    • Evaluar los efectos a largo plazo de mavacamten sobre los síntomas y las medidas ecocardiográficas de la función cardíaca en las cohortes de MAVERICK-LTE y de EXPLORER-LTE.
    • Evaluar la obstrucción del infundíbulo del ventrículo izquierdo (IVI) determinada mediante ecocardiografía Doppler en la cohorte EXPLORER-LTE.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Cardiac Magnetic Resonance Imaging Substudy - To assess the long-term effects of mavacamten on cardiac mass and structure as evaluated by cardiac magnetic resonance imaging (CMR)

    MAVERICK-LTE Participants
    At selected qualified sites, eligible participants will have the option to participate in the CMR substudy. It is anticipated that up to 40 participants will be enrolled. In addition to the main study schedule of procedures, participants will undergo CMR at Day 1 (predose) and Week 96.

    EXPLORER-LTE Participants
    At selected qualified sites, eligible individuals who participated in the EXPLORER-HCM CMR substudy will have the option to continue their participation; up to 80 participants will be enrolled. In addition to the main study schedule of procedures, these participants will undergo CMR at Week 24 and Week 96.
    Subestudio de resonancia magnética cardíaca: Evaluar el efecto a largo plazo de mavacamten sobre la masa y la estructura cardíacas evaluadas mediante resonancia magnética cardíaca (RMC).
    Participantes en el estudio MAVERICK-LTE
    En determinados centros cualificados, los participantes aptos tendrán la opción de participar en el subestudio de RMC. Se prevé la inclusión de hasta 40 participantes. Además del calendario de procedimientos del estudio principal, los participantes se someterán a una RMC el día 1 (antes de la dosis) y la semana 96.

    Participantes en el estudio EXPLORER-LTE
    En determinados centros cualificados, las personas aptas que participaron en el subestudio de RMC EXPLORER-HCM tendrán la opción de seguir participando; se inscribirá a como máximo 80 participantes. Además del calendario de procedimientos del estudio principal, estos participantes se someterán a una RMC en la semana 24 y la semana 96.
    E.3Principal inclusion criteria
    1. Has completed the Parent Study through to the EOS Visit within 90 days of signing consent. (Participants who are beyond the 90 day window from EOS Visit may be included in this study pending MyoKardia Medical Monitor approval)
    2. Is able to understand and comply with the study procedures, understand the risks involved in the study, and provide informed consent according to federal, local, and institutional guidelines before the first study-specific procedure
    3. Body weight is greater than 45 kg at the Screening Visit or Day 1 (Day 1 weight must be verified prior to dosing)
    4. Has adequate acoustic windows to enable accurate TTEs (refer to Echocardiography Site Instruction Manual)
    5. Has documented LVEF ≥ 50% by echocardiography core laboratory read of screening TTE at rest
    6. Has safety laboratory parameters within normal limits (according to the central laboratory reference range); however, a participant with safety laboratory parameters outside normal limits may be included if he or she meets all of the following criteria:
    • The safety laboratory parameter outside normal limits is considered by the Investigator to be clinically unimportant
    • If there is an alanine aminotransferase or aspartate aminotransferase result, the value must be < 3× the upper limit of the laboratory reference range
    • The body size–adjusted estimated glomerular filtration rate is ≥ 30 mL/min/1.73 m2
    7. Female participants must not be pregnant or lactating and, if sexually active, must use one of the following highly effective birth control methods from the Screening Visit through 90 days after the last dose of investigational medicinal product (IMP).
    • combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation or progestogen-only hormonal contraception associated with inhibition of ovulation by oral, implantable, or injectable route of administration
    • intrauterine device (IUD)
    • intrauterine hormone-releasing system (IUS)
    • bilateral tubal occlusion
    • Female is surgically sterile for 6 months or postmenopausal for 1 year. Permanent sterilization includes hysterectomy, bilateral oophorectomy, bilateral salpingectomy, and/or documented bilateral tubal occlusion at least 6 months prior to Screening. Females are considered postmenopausal if they have had amenorrhea for at least 1 year or more following cessation of all exogenous hormonal treatments and follicle stimulating hormone (FSH) levels are in the postmenopausal range.
    • In addition to the above contraceptive requirements for female participants, male partners must also use a contraceptive (eg, barrier, condom, or vasectomy)
    1. Ha completado el estudio original hasta la visita de FDE en los 90 días siguientes a la firma del consentimiento. (Los participantes que hayan superado el margen de 90 días desde la visita FDE podrán participar en este estudio previa aprobación del monitor médico de MyoKardia).
    2. Capacidad para entender y cumplir los procedimientos del estudio, comprender los riesgos que entraña el estudio y otorgar su consentimiento informado de conformidad con las normas federales, locales y del centro antes de realizar el primer procedimiento específico del estudio.
    3. Peso corporal superior a 45 kg en la visita de selección o el día 1 (el peso del día 1 deberá verificarse antes de la administración).
    4. Tiene ventanas acústicas suficientes para permitir ETT exactas (consulte el manual de instrucciones del centro para ecocardiografía)
    5. FEVI documentada ≥ 50 % según la evaluación del laboratorio central de ecocardiografía de la ETT de selección en reposo.
    6. Presencia de parámetros analíticos de seguridad dentro de los límites normales (según el intervalo de referencia del laboratorio central); sin embargo, podrá incluirse a un participante con parámetros analíticos de seguridad fuera de los límites normales siempre que cumpla todos los criterios siguientes:
    • El investigador considera que el parámetro analítico de seguridad situado fuera de los límites normales carece de importancia clínica.
    • Si existe un resultado de alanina aminotransferasa o aspartato aminotransferasa, el valor debe ser < 3 veces el límite superior del intervalo de referencia del laboratorio.
    • La filtración glomerular estimada ajustada por el tamaño corporal es ≥ 30 ml/min/1,73 m2.
    7. Las mujeres participantes no podrán estar embarazadas ni amamantando y, en caso de ser sexualmente activas, deben utilizar uno de los siguientes métodos anticonceptivos muy eficaces desde la visita de selección hasta 90 días después de la última dosis del medicamento en investigación (MEI).
    • anticonceptivos hormonales combinados (con estrógenos y progestágenos) asociados a inhibición de la ovulación o anticonceptivos hormonales solo con progestágenos asociados a inhibición de la ovulación por vía oral, implantable o inyectable.
    • dispositivo intrauterino (DIU)
    • sistema intrauterino (SIU) de liberación de hormonas
    • ligadura de trompas bilateral
    • Mujer que lleva seis meses esterilizada quirúrgicamente o un año en situación posmenopáusica. La esterilización permanente comprende histerectomía, ovariectomía bilateral, salpingectomía bilateral o ligadura de trompas bilateral documentada al menos seis meses antes de la selección. Se considera posmenopáusicas a las mujeres que han tenido amenorrea durante un año o más tras la interrupción de todos los tratamientos hormonales exógenos y cuyas concentraciones de folitropina (FSH) se encuentran dentro del intervalo posmenopáusico.
    • Además de los requisitos anticonceptivos anteriores para las mujeres participantes, las parejas masculinas también deberán utilizar un anticonceptivo (p. ej., de barrera, preservativo o vasectomía)
    E.4Principal exclusion criteria
    1. Has persistent or permanent atrial fibrillation not on anticoagulation for at least 4 weeks prior and/or is not adequately rate-controlled
    (Note: participants with persistent or permanent atrial fibrillation who are anticoagulated and adequately rate-controlled are allowed)
    2. Is currently taking, or has taken within 14 days of Screening, a prohibited medication such as a cytochrome P450 (CYP) 2C19 inhibitor (eg, omeprazole), a strong CYP 3A4 inhibitor, or St. John’s Wort (see APPENDIX 2 for more details)
    3. Has QTcF > 500 ms at Screening or any other ECG abnormality considered by the Investigator to pose a risk to participant safety (eg, second degree atrioventricular block type II)
    4. Has documented obstructive coronary artery disease (> 70% stenosis in one or more epicardial coronary arteries) or history of myocardial infarction
    5. Has known moderate or severe (as per Investigator’s judgment) aortic valve stenosis at Screening Visit
    6. Has hypersensitivity to any of the components of the mavacamten formulation
    7. Has participated in a clinical trial in which the participant received any investigational drug (or is currently using an investigational device) within 30 days prior to Screening, or at least 5 times the respective elimination half life (whichever is longer), except for participation in MAVERICK-HCM or EXPLORER-HCM
    8. Has a history of syncope or a history of sustained ventricular tachyarrhythmia with exercise between Parent Study EOS Visit and Screening Visit.
    9. Has a history of resuscitated sudden cardiac arrest or known history of appropriate implantable cardioverter-defibrillator (ICD) discharge for life-threatening ventricular arrhythmia between Parent Study EOS Visit and Screening Visit.
    (Note: history of anti-tachycardia pacing (ATP) is allowed)
    10. Currently treated with disopyramide or ranolazine (within 14 days prior to Screening Visit) or treatment with disopyramide or ranolazine is planned during the study
    11. Currently treated or planned treatment during the study with a combination of beta blocker and verapamil or a combination of beta blocker and diltiazem
    12. Has any acute or serious comorbid condition (eg, major infection or hematologic, renal, metabolic, gastrointestinal, or endocrine dysfunction) that, in the judgment of the Investigator, could lead to premature termination of study participation or interfere with the measurement or interpretation of the efficacy and safety assessments in the study
    13. History of clinically significant malignant disease that developed since enrollment in the Parent Study
    • Participants who have been successfully treated for nonmetastatic cutaneous squamous cell or basal cell carcinoma or have been adequately treated for cervical carcinoma in situ or breast ductal carcinoma in situ (DCIS) can be included in the study
    14. Is unable to comply with the study requirements, including the number of required visits to the clinical site
    15. Is employed by or is a relative of someone employed by MyoKardia, the Investigator, or his/her staff or family
    1. Presencia de fibrilación auricular persistente o permanente no tratada con anticoagulantes durante al menos cuatro semanas antes de la selección y/o con frecuencia cardiaca no controlada adecuadamente.
    (Nota: se permite la participación de participantes con fibrilación auricular persistente o permanente en tratamiento con anticoagulantes y con una frecuencia cardiaca controlada adecuadamente)
    2. Estar recibiendo actualmente, o en los 14 días previos a la selección, un medicamento prohibido, como un inhibidor del citocromo P450 (CYP) 2C19 (p. ej., omeprazol), un inhibidor potente del citocromo CYP 3A4 o hipérico (véanse más detalles en el APÉNDICE 2).
    3. Presenta un intervalo QTcF > 500 ms en la selección o cualquier otra anomalía en el ECG que el investigador considere que supone un riesgo para la seguridad del participante (por ej., bloqueo auriculoventricular de tipo II de segundo grado).
    4. Enfermedad coronaria obstructiva documentada (estenosis > 70 % en una o más arterias coronarias epicárdicas) o antecedentes de infarto de miocardio.
    5. Estenosis moderada o grave (según el criterio del investigador) de la válvula aórtica en la visita de selección.
    6. Presenta hipersensibilidad a cualquiera de los componentes de la formulación de mavacamten.
    7. Participación en un ensayo clínico en el que el participante haya recibido cualquier fármaco en investigación (o esté utilizando actualmente un dispositivo en investigación) en los 30 días previos a la selección o el equivalente a un mínimo de 5 veces la semivida de eliminación respectiva (lo que suponga más tiempo), excepto la participación en los estudios MAVERICK-HCM o EXPLORER-HCM.
    8. Antecedentes de síncope o de taquiarritmia ventricular sostenida con el ejercicio entre la visita FDE del estudio original y la visita de selección.
    9. Antecedentes de parada cardíaca súbita reanimada o antecedentes conocidos de descarga pertinente de un desfibrilador-cardioversor implantable (DCI) por una arritmia ventricular potencialmente mortal entre la visita de FDE del estudio original y la visita de selección.
    (Nota: se permiten los antecedentes de electroestimulación antitaquicardia (EAT)
    10. Tratamiento actual con disopiramida o ranolazina (en los 14 días previos a la visita de selección) o tratamiento con disopiramida o ranolazina previsto durante el estudio.
    11. Tratamiento actual o previsto durante el estudio con una combinación de betabloqueante y verapamilo o una combinación de betabloqueante y diltiazem.
    12. Presencia de una enfermedad concomitante aguda o grave (por ejemplo, infección importante o disfunción hematológica, renal, metabólica, digestiva o endocrina) que, en opinión del investigador, podría motivar la finalización prematura de la participación en el estudio o dificultar la obtención o interpretación de las evaluaciones de eficacia y seguridad del estudio.
    13. Antecedentes de neoplasia maligna clínicamente significativa aparecida desde la inclusión en el estudio original.
    • En el estudio podrán incluirse participantes que hayan sido tratados satisfactoriamente de un carcinoma espinocelular o basocelular cutáneo no metastásico o que hayan sido debidamente tratadas por un carcinoma cervicouterino in situ o carcinoma ductal de mama in situ.
    14. Incapacidad de cumplir los requisitos del estudio, incluido el número de visitas necesarias al centro clínico.
    15. Es empleado o familiar de una persona empleada por MyoKardia, el investigador, su personal o su familia.
    E.5 End points
    E.5.1Primary end point(s)
    12.3.2 Efficacy and Pharmacodynamic Endpoints
    1 Change from baseline in echocardiographic parameters of systolic function (eg, LVEF) and diastolic function (eg, peak velocity of early diastolic septal and lateral mitral annular motion [eꞌ], ratio of peak velocity of early diastolic transmitral flow [E] to eꞌ [E/eꞌ], ratio of E to peak velocity of late transmitral flow [A] [E/A], pulmonary artery systolic pressure, left atrium size) over time
    2 Change from baseline in resting and post-Valsalva LVOT gradient (EXPLORER-HCM participants only)
    3 Change from baseline in NYHA functional class over time
    4 Change from baseline in NT-proBNP over time
    5 Frequency of cardiac transplantation
    Eficacia y farmacodinamia
    1 Variación con respecto al momento basal de los parámetros ecocardiográficos de función sistólica (p. ej., FEVI) y diastólica (p. ej., velocidad máxima del movimiento [eꞌ] anular mitral lateral y septal diastólico, cociente entre la velocidad máxima del flujo transmitral diastólico precoz [E] y eꞌ [E/eꞌ], cociente entre E y la velocidad máxima del flujo transmitral tardío [A] [E/A], presión sistólica de la arteria pulmonar, tamaño de la aurícula izquierda) a lo largo del tiempo.
    2 Variación con respecto al momento basal del gradiente IVI en reposo y después de Valsalva (solo en los participantes en EXPLORER-HCM)
    3 Variación con respecto al momento basal de la clase funcional de la New York Heart Association (NYHA) a lo largo del tiempo.
    4 Variación de la NT-proBNP con respecto al período basal a lo largo del tiempo.
    5 Frecuencia de trasplante cardíaco
    E.5.1.1Timepoint(s) of evaluation of this end point
    1 Week 96/EOT
    2 Week 96/EOT
    3 Week 96/EOT
    4 Week 96/EOT
    5 EOT
    1 Semana 96/FDT
    2 Semana 96/FDT
    3 Semana 96/FDT
    4 Semana 96/FDT
    5 FDT
    E.5.2Secondary end point(s)
    CMR Substudy -
    For Participants from EXPLORER-HCM
    Primary Endpoint
    • Change from Week 24 to Week 96 in LV mass index
    Exploratory Endpoints
    • Change from Week 24 to Week 96 in myocardial fibrosis as measured by late gadolinium enhancement
    • Change from Week 24 to Week 96 in cellular hypertrophy, left atrial volume and function, and LV function

    For Participants from MAVERICK-HCM
    Primary Endpoint
    • Change from baseline to Week 96 in LV mass index
    Exploratory Endpoints
    • Change from baseline to Week 96 in myocardial fibrosis as measured by late gadolinium enhancement
    • Change from baseline to Week 96 in cellular hypertrophy, left atrial volume and function, and LV function
    Subestudio de RMC:
    Para los participantes del estudio EXPLORER-HCM
    Criterio de valoración principal
    • Variación entre la semana 24 y la semana 96 del índice de masa del ventrículo izquierdo.
    Criterios de valoración exploratorios
    • Variación entre la semana 24 y la semana 96 de la fibrosis miocárdica, medida mediante la captación tardía de gadolinio.
    • Variación entre la semana 24 y la semana 96 de la hipertrofia celular, el volumen y la función de la aurícula izquierda y la función del ventrículo izquierdo.

    Para participantes del estudio MAVERICK-HCM
    Criterio de valoración principal
    • Variación entre el momento basal y la semana 96 del índice de masa del ventrículo izquierdo.
    Criterios de valoración exploratorios
    • Variación entre el momento basal y la semana 96 de la fibrosis miocárdica, medida mediante la captación tardía de gadolinio.
    • Variación entre el momento basal y la semana 96 de la hipertrofia celular, el volumen y la función de la aurícula izquierda y la función del ventrículo izquierdo.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 96
    Semana 96
    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 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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 EEA51
    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
    Belgium
    Czech Republic
    Denmark
    France
    Germany
    Israel
    Italy
    Netherlands
    Poland
    Portugal
    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
    LVLS
    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 months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months1
    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: 238
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 42
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 280
    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)
    After patients have ended their participation in the trial, they will be treated according to the normal standard of care.
    Una vez los pacientes hayan finalizado su participación en el ensayo, serán tratados según el tratamiento habitual.
    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 Decision2019-08-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-24
    P. End of Trial
    P.End of Trial StatusOngoing
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