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    Summary
    EudraCT Number:2017-002530-23
    Sponsor's Protocol Code Number:MYK-461-005
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-11-10
    Trial results View 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 number2017-002530-23
    A.3Full title of the trial
    A Randomized, Double blind, Placebo controlled Clinical Study to Evaluate Mavacamten (MYK-461) in Adults with Symptomatic Obstructive Hypertrophic Cardiomyopathy
    Studio clinico randomizzato, in doppio cieco, controllato verso placebo per valutare mavacamten (MYK-461) in soggetti adulti con cardiomiopatia ipertrofica ostruttiva sintomatica
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate the safety and benefit of Mavacamten (MYK 461) in adults with an inherited heart disease causing thickening of the heart muscle
    Uno studio per valutare la sicurezza e il beneficio di Mavacamten (MYK 461) in adulti con una malattia cardiaca ereditaria che causa l'ispessimento della muscolatura cardiaca
    A.3.2Name or abbreviated title of the trial where available
    EXPLORER-HCM
    EXPLORER-HCM
    A.4.1Sponsor's protocol code numberMYK-461-005
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN00000000
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03470545
    A.5.3WHO Universal Trial Reference Number (UTRN)U0000-0000-0000
    A.5.4Other Identifiers
    Name:US IND Number Number:121904
    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 Address1000 Sierra Point Parkway
    B.5.3.2Town/ cityBrisbane
    B.5.3.3Post codeCA 94005
    B.5.3.4CountryUnited States
    B.5.4Telephone number0016507410900
    B.5.5Fax number0016507410900
    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 INNMavacamten
    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
    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 INNMavacamten
    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: 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 INNMavacamten
    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/g milligram(s)/gram
    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: 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 INNMavacamten
    D.3.9.2Current sponsor codeMYK-461
    D.3.9.3Other descriptive nameMavacamten
    D.3.9.4EV Substance CodeSUB161202
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    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.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, hard
    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
    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 compare the effect of a 30-week course of mavacamten with placebo
    on clinical response comprising of exercise capacity and clinical symptoms in participants with symptomatic obstructive hypertrophic cardiomyopathy (oHCM)
    Confrontare l¿effetto di un ciclo di mavacamten di 30 settimane con il placebo sulla risposta clinica comprendente la capacit¿ di esercizio e i sintomi clinici nei partecipanti con cardiomiopatia ipertrofica ostruttiva (CMIO) sintomatica
    E.2.2Secondary objectives of the trial
    To compare the effect of a 30-week course of mavacamten with placebo on symptoms and left ventricular outflow tract (LVOT) obstruction as determined by Doppler echocardiography
    To compare the effect of a 30-week course of mavacamten with placebo on exercise capacity, clinical symptoms and Patient Reported Outcomes individually
    To assess the safety and tolerability of mavacamten
    To assess the pharmacokinetic (PK) characteristics of mavacamten
    Confrontare l¿effetto di un ciclo di mavacamten di 30 settimane con il placebo sui sintomi e sull¿ostruzione del tratto di efflusso del ventricolo sinistro (LVOT) determinata mediante ecocardiogramma Doppler
    Confrontare l¿effetto di un ciclo di mavacamten di 30 settimane con il placebo sulla capacit¿ di esercizio, sui sintomi clinici e sugli esiti riferiti dal paziente singolarmente
    Valutare la sicurezza e la tollerabilit¿ di mavacamten
    Valutare le caratteristiche farmacocinetiche (pharmacokinetic, [PK]) di mavacamten
    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: Substudy is described in main protocol.
    Substudy objective will be to assess the effect of mavacamten on cardiac mass and structure as evaluated by cardiac magnetic resonance imaging (CMR).
    At selected sites, participants will have the option to participate in the CMR substudy. Approximately 80 participants will be enrolled (~40 per treatment group). In addition to the main study schedule of procedures, participants will undergo CMR at Day 1 and Week 30 (or up to 5 days before each visit).

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Il sottostudio è descritto nel protocollo principale.
    L'obiettivo del sottostudio è valutare l'effetto di mavacamten sulla massa e sulla cardiaca misurate mediante risonanza magnetica cardiaca (RMC)
    Presso i centri selezionati, i partecipanti avranno la possibilità di partecipare al sottostudio di risonanza magnetica cardiovascolare (Cardiovascular magnetic resonance, [CMR]). Saranno arruolati all’incirca 80 partecipanti (~40 per gruppo di trattamento). In aggiunta al calendario delle procedure dello studio principale, i partecipanti saranno sottoposti a CMR il Giorno 1 e la Settimana 30 (o fino a 5 giorni prima di ogni visita).
    E.3Principal inclusion criteria
    1.Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent according to federal, local, and institutional guidelines before the first
    study specific procedure
    2.Is at least 18 years old at Screening
    3.Body weight is greater than 45 kg at Screening
    4.Has adequate acoustic windows to enable accurate TTEs (Refer to
    Echocardiography Site Instruction Manual)
    5.Diagnosed with oHCM consistent with current AACF/AMA and ESC guidelines, ie, satisfy both criteria below (criteria to be documented by the echocardiography core laboratory):
    A.Has unexplained left ventricular (LV) hypertrophy with nondilated ventricular chambers in the absence of other cardiac (eg, hypertension, aortic stenosis) or systemic disease and with maximal LV wall thickness
    =15 mm (or =13 mm with positive family history of hypertrophic cardiomyopathy [HCM]), , as determined by core lab interpretation ,and
    B.Has LVOT peak gradient =50 mmHg during Screening as assessed by echocardiography at rest, after Valsalva maneuver, or postexercise (confirmed by echocardiography core laboratory interpretation)
    6.Has documented left ventricular ejection fraction (LVEF) =55% by echocardiography core laboratory read of Screening TTE at rest
    7. Has LVOT gradient with Valsalva maneuver at Screening TTE of =30 mmHg, determined by echocardiography core laboratory
    8.Has New York Heart Association (NYHA) funtional Class II or III symptoms at
    Screening
    9.Has documented oxygen saturation at rest =90% at Screening
    10.Is able to perform an upright CPET and has a respiratory exchange ratio (RER) =1.0 at Screening per central reading; if the RER is between
    0.91 and 1.0, the participant may be enrolled only if it is determined by the central CPET laboratory that peak exercise has been achieved in the subject (the only permitted reasons for subpeak performance are [1] a decrease in systolic blood pressure or [2] severe angina as described in the CPET Laboratory Manual)
    111.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 3 months after the last dose of
    investigational medicinal product (IMP).
    • combined (estrogen- and progestogen-containing) hormonal
    contraception associated with inhibition of ovulation or progestogenonly
    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 levels are in the postmenopausal range.
    Male
    partners must also use a contraceptive (eg, barrier, condom or
    vasectomy)
    1. Capacità di comprendere e rispettare le procedure dello studio, comprendere i rischi che comporta lo studio e fornire il consenso informato scritto secondo le linee guida federali, locali e istituzionali prima dell’esecuzione della prima procedura specifica dello studio
    2. Almeno 18 anni d’età allo screening
    3. Peso corporeo superiore a 45 kg allo screening
    4. Finestra acustica adeguata per permettere TTE accurati
    5. Diagnosi di oHCM coerente con le attuali linee guida dell'American College of Cardiology Foundation/American Heart Association e della European Society of Cardiology, ovvero soddisfare entrambi i criteri di seguito (criteri da documentare da parte del laboratorio ecocardiografico centrale):
    A. Ipertrofia ventricolare sinistra (LV) ingiustificata con camere ventricolari non dilatate in assenza di altra malattia cardiaca (ad esempio, ipertensione, stenosi aortica) o sistemica e con uno spessore massimo della parete ventricolare sinistra =15 mm (o =13 mm con anamnesi familiare positiva di cardiomiopatia ipertrofica [HCM]), e
    B. Gradiente di picco per LVOT =50 mmHg durante lo screening valutato mediante ecocardiografia a riposo, dopo manovra di Valsalva, o post sforzo (conferma mediante interpretazione da parte del laboratorio ecocardiografico centrale)
    6. Frazione di eiezione ventricolare sinistra (LVEF) =55% documentata mediante lettura del TTE allo screening da parte del laboratorio ecocardiografico centrale
    7. Sintomi di Classe II o III secondo la New York Heart Association (NYHA) allo screening
    8. Saturazione dell’ossigeno a riposo =90% documentata allo screening
    9. Capacità di eseguire un CPET in posizione eretta e rapporto di scambio respiratorio (RER) pari a =1,0 allo screening secondo la lettura centrale; se il RER è compreso tra 0,91 e 1,0, il/la partecipante può essere arruolato/a solo se il laboratorio centrale per CPETstabilisca che il soggetto ha raggiunto il picco dello sforzo (gli unici motivi consentiti per un prestazione al di sotto del picco sono [1] una diminuzione della pressione arteriosa sistolica o [ 2] angina grave come descritto nel manuale di laboratorio per CPET)
    10. Le partecipanti di sesso femminile non devono essere in stato di gravidanza o di allattamento e, se sessualmente attive, devono utilizzare uno dei seguenti metodi contraccettivi accettabili dalla visita di screening fino a 3 mesi dopo l'ultima dose di farmaco sperimentale (IMP). I contraccettivi ormonali non sono considerati contraccezione altamente efficace per questo studio poiché mavacamten potrebbe ridurre l'efficacia dei contraccettivi ormonali.
    • Metodo a doppia barriera (ad es., vasectomia o uomo che utilizza il preservativo e donna che utilizza il diaframma o il cappuccio cervicale)
    • Barriera (ad es., uomo che utilizza il preservativo) in associazione all’ utilizzo da parte della donna di un dispositivo intrauterino non ormonale o di un sistema intrauterino
    • Donna chirurgicamente sterile da 6 mesi o in stato di post-menopausa da 2 anni. La sterilizzazione permanente include isterectomia, ooforectomia bilaterale, salpingectomia bilaterale e/o occlusione bilaterale delle tube documentata almeno 6 mesi prima dello screening. Le donne sono considerate in stato di post-menopausa se presentano amenorrea da almeno 2 anni o più a seguito dell’interruzione di tutti i trattamenti ormonali esogeni e i livelli dell'ormone follicolo-stimolante rientrano nell'intervallo della post-menopausa
    11. I partecipanti di sesso maschile con partner sessuali devono accettare di utilizzare preservativi per l'intera durata dello studio e per 3 mesi dopo l'ultima dose di IMP al fine di prevenire il passaggio di mavacamten alla partner attraverso l’eiaculato
    E.4Principal exclusion criteria
    1.Previously participated in a clinical study with mavacamten
    2.Hypersensitivity to any of the components of the mavacamten formulation
    3.Participated in a clinical trial in which the participant received any investigational drug (or is currently using an investigational device) within 30 days of Screening, or at least 5x the respective elimination half life (whichever is longer)
    4.Infiltrative or storage disorder causing CH that mimics oHCM, such as
    Fabry disease, amyloidosis, or Noonan syndrome with LVH
    5.Medical condition that precludes upright exercise stress testing
    6.History of syncope or sustained VT with exercise within 6 months prior to Screening
    7.History of resuscitated sudden CA (at any time) or history of appropriate ICD discharge for life-threatening VA within 6 months prior to Screening
    8.Has paroxysmal, intermittent AF with AF present per the investigator's evaluation of the participant's ECG at time of Screening
    9.Has persistent/permanent AF not on anticoagulation for at least 4 weeks to Screening &/or not adequately rate controlled within 6 months prior to Screening
    10.Current treatment (within 14 days to Screening) or planned treatment during the study with disopyramide or ranolazine
    11.Current treatment (within 14 days prior to Screening) or planned treatment during the study with a combination of ß-blockers and verapamil or a combination of ß-blockers and diltiazem
    12.Individuals on ß-blockers, verapamil, or diltiazem, any dose adjustment of that medication <14 days to Screening or any anticipated change in treatment regimen using these medications during the study
    13.Has LVOT gradient with Valsalva maneuver <30 mmHg at Screening
    TTE
    14.Successfully treated with ISR (surgical myectomy or percutaneous alcohol septal ablation [ASA]) within 6 months prior to Screening or plans to have either of these treatments during the study
    15.ICD placement within 6 months prior to Screening or planned ICD
    placement during study
    16.Has QT interval with Fridericia correction (QTcF) >480 ms or other ECG abnormality considered by investigator to pose risk to participant safety (eg, second-degree atrioventricular block type II)
    17.Documented OCAD (>70% stenosis in one or more epicardial coronary arteries) or history of MI
    18.Moderate or severe (as per investigator's judgment) AVS at
    Screening
    19.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 & safety assessments in the study
    20.Has pulmonary disease that limits exercise capacity or systemic arterial oxygen saturation
    21.History of clinically significant malignant disease within 10 years of
    Screening:
    •Who have been successfully treated for nonmetastatic cutaneous squamous cell or basal cell carcinoma or been adequately treated for cervical carcinoma in situ can be included in the study
    •With other malignancies who are cancer free for more than 10 years before Screening can be included in the study
    22.Has safety laboratory parameters (chemistry, hematology, coagulation, & urinalysis) outside normal limits (according to the central laboratory reference range) at Screening as assessed by the central laboratory; however, participant with safety laboratory parameters outside normal limits may be included if he or she meets all of the following criteria:
    •Safety laboratory parameter outside normal limits is considered by the investigator to be clinically not significant
    •If there is an alanine aminotransferase or aspartate aminotransferase result, the value must be <3 × the upper limit of the laboratory reference range
    •Body size–adjusted estimated glomerular filtration rate is =30
    mL/min/1.73 m2
    1. Precedente partecipazione a uno studio clinico con mavacamten
    2. Ipersensibilità a uno dei componenti della formulazione di mavacamten
    3. Partecipazione a una sperimentazione clinica in cui il/la partecipante riceveva un farmaco sperimentale (o sta attualmente utilizzando un dispositivo sperimentale) entro 30 giorni prima dello Screening, o almeno 5 volte la rispettiva emivita di eliminazione (a seconda di quale sia il periodo più lungo)
    4. Nota malattia infiltrativa o da accumulo che causa ipertrofia cardiaca somigliante all’OHCM, ad esempio malattia di Fabry, amiloidosi o sindrome di Noonan con ipertrofia del ventricolo sinistro LV
    5. Qualsiasi condizione medica che preclude i test da stress sotto sforzo in posizione eretta
    6. Anamnesi di sincope o tachiaritmia ventricolare sostenuta sotto sforzo nei 6 mesi precedenti lo screening
    7. Anamnesi di arresto cardiaco improvviso con rianimazione (in qualsiasi momento) o anamnesi nota di scariche appropriate erogate dal defibrillatore cardioverter impiantabile (ICD) per aritmia ventricolare potenzialmente fatale nei 6 mesi precedenti lo screening
    8. Fibrillazione atriale parossistica intermittente con presenza di fibrillazione atriale secondo la valutazione dello sperimentatore dell’ECG del/la partecipante al momento dello screening
    9. Fibrillazione atriale permanente o persistente non trattata con anticoagulanti da almeno 4 settimane prima dello screening e/o senza adeguato controllo della frequenza nei 6 mesi precedenti lo screening (Nota: i pazienti con fibrillazione atriale persistente o permanente che sono in trattamento con anticoagulanti e la cui frequenza è adeguatamente controllata sono ammessi)
    10. Trattamento attuale (entro i 14 giorni precedenti lo screening) o trattamento programmato durante lo studio con disopiramide o ranolazina
    11. Trattamento attuale (entro i 14 giorni precedenti lo screening) o trattamento programmato durante lo studio con una combinazione di ß-bloccanti e verapamil o una combinazione di ß-bloccanti e diltiazem
    12. Per i soggetti in trattamento con ß-bloccanti, verapamil, o diltiazem, qualsiasi regolazione della dose di quel farmaco <14 giorni prima dello screening o qualsiasi modifica prevista nel regime di trattamento utilizzando questi farmaci durante lo studio
    13. Gradiente LVOT con manovra di Valsalva <30 mmHg al TTE dello screening
    14. Soggetto trattato con efficacementecon riduzione invasiva del setto (miectomia chirurgica o ablazione alcolica percutanea del setto [ASA]) nei 6 mesi precedenti lo screening o che ha in programma di sottoporsi a uno di questi trattamenti durante lo studio (nota: gli individui che si sono sottoposti senza successo a miectomia o procedura percutanea ASA eseguite >6 mesi prima dello screening potranno essere arruolati se i criteri di eleggibilità dello studio relativi al gradiente LVOT vengono soddisfatti)
    15. Inserimento dell’ICD entro 6 mesi prima dello screening o inserimento dell’ICD programmato durante lo studio
    16. Intervallo QT corretto con il metodo Fridericia (QTcf) >480 ms o qualsiasi altra anomalia all'ECG che lo sperimentatore ritiene possa rappresentare un rischio per la sicurezza del/la partecipante (ad es. blocco atrioventricolare di secondo grado tipo II)
    17. Coronaropatia ostruttiva documentata (stenosi al >70% in una o più arterie coronarie epicardiche) o anamnesi di infarto miocardico
    18. Stenosi valvolare aortica nota moderata o grave (a giudizio dello sperimentatore) allo screening
    19. Comorbilità acuta o grave (ad es., importante infezione o disfunzione ematologica, renale, metabolica, gastrointestinale o endocrina) che, secondo il giudizio dello sperimentatore, potrebbe portare a interruzione anticipata della partecipazione allo studio o interferiri laboratorio di sicurezza che non rientrano nei limiti della norma potrà essere incluso/a se soddisfa tutti i criteri seguenti:e con la misurazione o l'interpretazione delle valutazioni di efficacia e sicurezza nello studio
    E.5 End points
    E.5.1Primary end point(s)
    •Clinical response defined as achieving (1) an improvement of 1.5 mL/kg/min or more in peak oxygen consumption (pVO2) as determined by CPET, & (2) a reduction of one or more class in NYHA Functional Classification, at the end of Week 30 dosing period
    Risposta clinica, definita come raggiungimento (1) di un miglioramento =1,5 ml/kg/min nel consumo massimo di ossigeno (pVO2) determinato mediante test da sforzo cardiopolmonare (cardiopulmonary exercise test, [CPET]) e (2) una riduzione di una o più classi nella Classificazione funzionale della New York Heart Association (NYHA) alla fine del periodo di dosaggio della Settimana 30
    E.5.1.1Timepoint(s) of evaluation of this end point
    30 Weeks
    30 Settimane
    E.5.2Secondary end point(s)
    1. Change from baseline to Week 30 in post-exercise LVOT peak gradient
    2. Proportion of participants with at least 1 class improvement in NYHA functional class from baseline to Week 30
    3. Change from baseline to Week 30 in peak oxygen consumption (pVO2) as determined by CPET
    4. Change from baseline to Week 30 in patient-reported severity of HCM symptoms as assessed by the HCM Symptom Questionnaire score
    5.Change from baseline to Week 30 in participant-reported health related quality of life as assessed by the KCCQ score
    1. Variazione dal basale alla Settimana 30 nel picco del gradiente post-esercizio in corrispondenza del LVOT
    2. Percentuale di partecipanti con miglioramento di almeno 1 classe nella classe funzionale NYHA, dal basale alla Settimana 30
    3. Variazione dal basale alla Settimana 30 nel consumo massimo d¿ossigeno (pVO2) determinato mediante CPET
    4. Variazione dal basale alla Settimana 30 nella gravit¿ riferita dal paziente dei sintomi della CMI valutati in base al punteggio del Questionario sui sintomi della CMI
    5. Variazione dal basale alla Settimana 30 nella qualità della vita correlata allo stato di salute riferita dal partecipante, valutata attraverso effettuate il punteggio ottenuto del Questionario di Kansas City per la Cardiomiopatia (Kansas City Cardiomyopathy Questionnaire, [KCCQ])
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Week 30
    2. Week 30
    3. Week 30
    4. Week 30
    5. Week 30
    6. Week 30
    1. Settimana 30
    2. Settimana 30
    3. Settimana 30
    4. Settimana 30
    5. Settimana 30
    6. Settimana 30
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA38
    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
    Belgium
    Czechia
    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 years2
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months2
    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: 187
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 33
    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 220
    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 volta che i pazienti avranno terminato 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 Decision2018-08-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-09-11
    P. End of Trial
    P.End of Trial StatusCompleted
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