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    Summary
    EudraCT Number:2018-004039-64
    Sponsor's Protocol Code Number:MYK-461-007
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-12-28
    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 number2018-004039-64
    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)
    Studio di estensione di sicurezza a lungo termine di Mavacamten (MYK 461) in soggetti adulti con cardiomiopatia ipertrofica che hanno completato le sperimentazioni MAVERICK-HCM (MYK-461-006) o EXPLORER-HCM (MYK 461 005) (MAVA-LTE)
    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)
    Studio di estensione di sicurezza a lungo termine di Mavacamten (MYK 461) in soggetti adulti con cardiomiopatia ipertrofica che hanno completato le sperimentazioni MAVERICK-HCM (MYK-461-006) o EXPLORER-HCM (MYK 461 005) (MAVA-LTE)
    A.3.2Name or abbreviated title of the trial where available
    MAVA-LTE
    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 number16507410900
    B.5.5Fax number00000000
    B.5.6E-mailmedinfo@myokardia.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, 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 INNNA
    D.3.9.1CAS number 00-00-0
    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 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.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, 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 INNNA
    D.3.9.1CAS number 00-00-0
    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 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.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, 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 INNNA
    D.3.9.1CAS number 00-00-0
    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 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.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, 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 INNNA
    D.3.9.1CAS number 00-00-0
    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 µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2500
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hypertrophic Cardiomyopathy.
    Cardiomiopatia Ipertrofica.
    E.1.1.1Medical condition in easily understood language
    -Inherited heart disease causing thickening of the muscle wall of the heart.
    -Cardiopatia ereditaria che provoca l'ispessimento della parete muscolare del cuore.
    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.
    • Valutare la sicurezza e la tollerabilità a lungo termine di Mavacamten nei partecipanti con HCM precedentemente arruolati in 1 delle 2 sperimentazioni controllate verso placebo: MAVERICK-HCM per nHCM ed EXPLORER-HCM per oHCM.
    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.
    • Valutare nelle coorti MAVERICK-LTE ed EXPLORER-LTE gli effetti a lungo termine di Mavacamten sui sintomi e sulle misure ecocardiografiche della funzione cardiaca.
    • Valutare l’ostruzione del tratto LVOT come determinato mediante ecocardiografia doppler nella coorte 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

    Other types of substudies
    Specify title, date and version of each substudy with relative objectives: Cardiac Magnetic Resonance Imaging Substudy - To assess the longterm 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.

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Sottostudio di risonanza magnetica cardiaca - Valutare gli effetti a lungo termine di Mavacamten sulla massa e sulla struttura cardiache come valutato mediante risonanza magnetica cardiaca (CMR)

    Partecipanti allo studio MAVERICK-LTE
    Presso centri abilitati selezionati, i partecipanti idonei avranno la possibilità di partecipare al sottostudio di CMR. Si prevede l’arruolamento di un massimo di 40 partecipanti. In aggiunta al programma delle procedure dello studio principale, i partecipanti saranno sottoposti a CMR il Giorno 1 (prima della dose) e la Settimana 96.

    Partecipanti allo studio EXPLORER-LTE
    Presso centri abilitati selezionati, i soggetti idonei che hanno partecipato al sottostudio CMR dello studio EXPLORER-HCM avranno la possibilità di proseguire la loro partecipazione; saranno arruolati fino a 80 partecipanti. In aggiunta al programma delle procedure dello studio principale, questi partecipanti saranno sottoposti a CMR la Settimana 24 e la Settimana 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)
    Ogni partecipante deve soddisfare i seguenti criteri per essere incluso/a in questo studio:
    1. Ha completato lo Studio originario fino alla Visita EOS entro 90 giorni dalla firma del consenso. (I/le partecipanti che sono oltre la finestra di 90 giorni dalla Visita EOS potranno essere inclusi/e in questo studio in attesa dell’approvazione del Responsabile del monitoraggio medico di MyoKardia).
    2. È in grado di comprendere e attenersi alle procedure dello studio, comprendere i rischi che lo studio comporta e fornire il consenso informato secondo le linee guida centrali, locali e istituzionali prima della prima procedura specifica per lo studio.
    3. Il peso corporeo è superiore a 45 kg alla Visita di screening o al Giorno 1 (il peso del Giorno 1 deve essere verificato prima del dosaggio).
    4. Ha finestre acustiche adeguate per consentire TTE accurate (consulti il Manuale di istruzioni ecocardiografiche del centro)
    5. Ha un valore LVEF = 50% documentato dalla lettura della TTE a riposo allo screening effettuata da parte del laboratorio ecocardiografico centrale.
    6. Ha parametri di laboratorio di sicurezza entro i limiti di normalità (sulla base dell’intervallo di riferimento del laboratorio centrale); tuttavia, un/a partecipante con parametri di laboratorio di sicurezza al di fuori dei limiti di normalità può essere incluso/a laddove soddisfi tutti i seguenti criteri:
    • Il parametro di laboratorio di sicurezza al di fuori dei limiti di normalità è considerato clinicamente non significativo dallo Sperimentatore
    • In presenza di un risultato di alanina aminotransferasi o aspartato aminotransferasi, il valore deve essere < 3 volte il limite superiore di normalità dell’intervallo di riferimento del laboratorio
    • La velocità di filtrazione glomerulare stimata corretta per le dimensioni corporee è = 30 mL/min/1,73 m2
    7. Le partecipanti di sesso femminile non devono essere in gravidanza o allattamento e, se sessualmente attive, devono utilizzare uno dei seguenti metodi contraccettivi altamente efficaci dalla Visita di screening fino a 90 giorni dopo l’ultima dose di Prodotto medicinale sperimentale (investigational medicinal product, [IMP]).
    • contraccezione ormonale combinata (contenente estrogeno e progesterone) associata a inibizione dell’ovulazione o contraccezione ormonale contenente solo progesterone associata a inibizione dell’ovulazione per via di somministrazione orale, impiantabile o iniettabile
    • dispositivo intrauterino (intrauterine device, [IUD])
    • sistema intrauterino a rilascio di ormoni (intrauterine system, [IUS])
    • occlusione tubarica bilaterale
    • La donna è resa chirurgicamente sterile da 6 mesi o in post-menopausa da 1 anno. La sterilizzazione permanente comprende l’isterectomia, l’ooforectomia bilaterale, la salpingectomia bilaterale e/o l’occlusione tubarica bilaterale documentata eseguite almeno 6 mesi prima dello Screening. Le donne sono considerate in post-menopausa se presentano amenorrea da almeno 1 anno o più dopo la cessazione di tutti i trattamenti ormonali esogeni e i livelli di ormone follicolo-stimolante (follicle stimulating hormone, [FSH]) sono nell’intervallo post-menopausale.
    • In aggiunta ai requisiti contraccettivi di cui sopra per le partecipanti di sesso femminile, i partner di sesso maschile devono utilizzare anche un metodo contraccettivo (ad es. metodo barriera, preservativo o vasectomia).
    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
    Un/a partecipante che soddisfi qualsiasi dei seguenti criteri di esclusione non può partecipare a questo studio:
    1. Ha fibrillazione atriale persistente o permanente non sottoposta a terapia anticoagulante per almeno 4 settimane precedenti e/o con controllo inadeguato della frequenza
    (Nota: sono ammessi i/le partecipanti con fibrillazione atriale persistente o permanente sottoposti a terapia anticoagulante e con controllo adeguato della frequenza)
    2. Sta attualmente assumendo, o ha assunto entro 14 giorni dallo Screening, un farmaco vietato, come un inibitore del citocromo P450 (CYP) 2C19 (ad es. omeprazolo), un inibitore forte di CYP 3A4 o l’iperico (consulti l’APPENDICE 2 per maggiori dettagli)
    3. Ha un intervallo QT con correzione di Fridericia (QTcF) > 500 ms allo Screening o qualsiasi altra anomalia dell’ECG che lo Sperimentatore ritiene che possa comportare un rischio per la sicurezza del/la partecipante (ad es. blocco atrioventricolare di secondo grado di tipo II)
    4. Ha una coronaropatia ostruttiva documentata (stenosi > 70% in una o più arterie coronarie epicardiche) o un’anamnesi di infarto del miocardio
    5. Ha una stenosi nota della valvola aortica moderata o grave (in base al giudizio dello Sperimentatore) alla Visita di screening
    6. Ha un’ipersensibilità a uno qualsiasi dei componenti della formulazione di mavacamten
    7. Ha partecipato a uno studio clinico in cui il/la partecipante ha ricevuto qualsiasi farmaco sperimentale (o in cui sta attualmente utilizzando un dispositivo sperimentale) entro 30 giorni precedenti lo Screening, o almeno 5 volte la rispettiva emivita di eliminazione (a seconda di quale sia il periodo più lungo), ad eccezione della partecipazione allo studio MAVERICK-HCM o EXPLORER-HCM
    8. Ha un’anamnesi di sincope o un’anamnesi di tachiaritmia ventricolare sostenuta con esercizio fisico tra la Visita EOS dello Studio originario e la Visita di screening
    9. Ha un’anamnesi di arresto cardiaco improvviso sottoposto a rianimazione o un’anamnesi nota di terapia di defibrillazione appropriata con defibrillatore cardiaco impiantabile (implantable cardioverter-defibrillator, [ICD]) per aritmia ventricolare potenzialmente letale tra la Visita EOS dello Studio originario e la Visita di screening
    (Nota: l’anamnesi di stimolazione antitachicardica [ATP] è consentita)
    10. Attualmente è trattato/a con disopiramide o ranolazina (entro i 14 giorni precedenti la Visita di screening) o il trattamento con disopiramide o ranolazina è programmato durante lo studio
    11. Attualmente è trattato/a o il trattamento è programmato durante lo studio con una combinazione di beta-bloccante e verapamil o una combinazione di beta-bloccante e diltiazem
    12. Ha qualsiasi comorbilità acuta o seria (ad es. infezione grave o disfunzione ematologica, renale, metabolica, gastrointestinale o endocrina) che, a giudizio dello Sperimentatore, potrebbe comportare un’interruzione anticipata della partecipazione allo studio o interferire con la misurazione o l’interpretazione delle valutazioni di efficacia e sicurezza eseguite nell’ambito dello studio
    13. Anamnesi di malattia maligna clinicamente significativa che si è sviluppata a partire dall’arruolamento nello Studio originario
    • I/le partecipanti trattati/e con successo per carcinoma cutaneo squamocellulare o basocellulare non metastatico o adeguatamente trattati/e per carcinoma cervicale in situ o carcinoma duttale in situ (ductal carcinoma in situ, [DCIS]) della mammella possono essere inclusi/e nello studio
    14. È incapace di rispettare i requisiti dello studio, incluso il numero di visite richieste presso il centro clinico
    15. È dipendente o familiare di un/a dipendente di MyoKardia, dello Sperimentatore o del suo personale o della sua famiglia
    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 [e¿], ratio of peak velocity of early diastolic transmitral flow [E] to e¿ [E/e¿], 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
    Efficacia e farmacodinamica
    • Variazione rispetto al basale nei parametri ecocardiografici della funzione sistolica (ad es. LVEF) e funzione diastolica (ad es. velocità di picco del flusso settale diastolico precoce e del flusso anulare mitralico laterale [e¿], rapporto tra la velocità di picco del flusso transmitralico diastolico precoce [E] e la velocità e¿ [E/e¿], rapporto tra la velocità E e la velocità di picco del flusso transmitralico tardivo [A] [E/A], pressione arteriosa polmonare sistolica, dimensioni dell’atrio sinistro) nel tempo
    • Variazione rispetto al basale nel valore del gradiente LVOT a riposo e post-Valsalva (solo per i/le partecipanti allo studio EXPLORER-HCM)
    • Variazione rispetto al basale in base classe funzionale nel tempo dell’Associazione dei cardiologi di New York (New York Heart Association, [NYHA])
    • Variazione rispetto al basale del valore di NT-proBNP nel tempo
    • Frequenza di trapianto cardiaco
    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 Settimana 96/EOT
    2 Settimana 96/EOT
    3 Settimana 96/EOT
    4 Settimana 96/EOT
    5 EOT
    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
    Sottostudio CMR
    Per i/le partecipanti provenienti dallo studio EXPLORER-HCM
    Endpoint primario
    • Variazione dalla Settimana 24 alla Settimana 96 nell’indice di massa ventricolare sinistra (VS)
    Endpoint esplorativi
    • Variazione dalla Settimana 24 alla Settimana 96 nella fibrosi miocardica, come misurata mediante enhancement tardivo con gadolinio
    • Variazione dalla Settimana 24 alla Settimana 96 nell’ipertrofia cellulare, nel volume e nella funzione atriale sinistra e nella funzione VS

    Per i/le partecipanti provenienti dallo studio MAVERICK-HCM
    Endpoint primario
    • Variazione dal basale alla Settimana 96 nell’indice di massa VS
    Endpoint esplorativi
    • Variazione dal basale alla Settimana 96 nella fibrosi miocardica, come misurata mediante enhancement tardivo con gadolinio
    • Variazione dal basale alla Settimana 96 nell’ipertrofia cellulare, nel volume e nella funzione atriale sinistra e nella funzione VS
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 96
    Settimana 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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    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 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
    Israel
    United States
    Belgium
    Czechia
    Denmark
    France
    Germany
    Italy
    Netherlands
    Poland
    Portugal
    Spain
    United Kingdom
    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 state15
    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.
    Dopo che i pazienti avranno concluso la loro partecipazione alla sperimentazione, saranno trattati secondo il normale standard di cura.
    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 Decision2019-05-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-08
    P. End of Trial
    P.End of Trial StatusOngoing
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