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    Summary
    EudraCT Number:2021-003536-92
    Sponsor's Protocol Code Number:CY6031
    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:2022-03-11
    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 number2021-003536-92
    A.3Full title of the trial
    A Phase 3, Multi-Center, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of CK-3773274 in Adults with Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction
    Ensayo en fase III, multicéntrico, aleatorizado, con doble enmascaramiento y comparativo con placebo para evaluar la eficacia y la seguridad de CK­3773274 en adultos con miocardiopatía hipertrófica sintomática y obstrucción del infundíbulo del ventrículo izquierdo
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 trial to measure how safe and effective CK3773274 is in Adults with obstructive hypertrophic cardiomyopathy (oHCM)
    Un ensayo de fase 3 para medir cuan seguro y efectivo es CK3773274 en adultos con miocardiopatía hipertrófica obstructiva (oHCM)
    A.4.1Sponsor's protocol code numberCY6031
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT05186818
    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 SponsorCytokinetics, 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 supportCytokinetics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCytokinetics Inc
    B.5.2Functional name of contact pointMedical Affairs
    B.5.3 Address:
    B.5.3.1Street Address350 Oyster Point Boulevard
    B.5.3.2Town/ citySouth San Francisco CA
    B.5.3.3Post code94080
    B.5.3.4CountryUnited States
    B.5.4Telephone number+16506242929
    B.5.6E-mailmedicalaffairs@cytokinetics.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 nameaficamten
    D.3.2Product code CK-3773274
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNaficamten
    D.3.9.1CAS number 2364554-48-1
    D.3.9.2Current sponsor codeCK-3773274
    D.3.9.3Other descriptive name(R)-N-(5-(5-ETHYL-1,2,4-OXADIAZOL-3-YL)-2,3-DIHYDRO-1H-INDEN-1-YL)-1-METHYL-1H-PYRAZOLE-4-CARBOXAMIDE
    D.3.9.4EV Substance CodeSUB197451
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    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
    obstructive hypertrophic cardiomyopathy (oHCM)
    miocardiopatía hipertrófica obstructiva (MHO)
    E.1.1.1Medical condition in easily understood language
    heart disease with thickening of the heart muscle
    enfermedad cardíaca con engrosamiento del músculo cardíaco
    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 evaluate the effect of CK-3773274 on exercise capacity in patients with symptomatic oHCM
    Evaluar el efecto de CK­3773274 sobre la capacidad de esfuerzo en pacientes con OMH sintomática
    E.2.2Secondary objectives of the trial
    - To evaluate the effect of CK-3773274 on patient health status
    - To evaluate the effect of CK-3773274 on New York Heart Association (NYHA) Functional Classification
    - To evaluate the effect of CK-3773274 on post-Valsalva left ventricular outflow tract gradients (LVOT-G)
    - To evaluate the effect of CK-3773274 on exercise capacity

    Safety
    To evaluate the safety and tolerability profile of CK-3773274 in patients with symptomatic oHCM
    -Evaluar el efecto de CK­3773274 en el estado de salud del paciente
    -Evaluar el efecto de CK­3773274 en la clasificación funcional de la New York Heart Association (NYHA)
    -Evaluar el efecto de CK­3773274 en los gradientes del infundíbulo del ventrículo izquierdo (GIVI) después de realizar la maniobra de Valsalva
    -Evaluar el efecto de CK­3773274 sobre la capacidad de esfuerzo
    Seguridad
    -Evaluar el perfil de seguridad y tolerabilidad de CK­3773274 en pacientes con OMH sintomática
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    A Cardiac Magnetic Resonance (CMR) imaging sub-study will be open to approximately 100 patients who consent to participate.
    Un subestudio de imágenes de resonancia magnética cardíaca (RMC) estará abierto para aproximadamente 100 pacientes que den su consentimiento para participar.
    E.3Principal inclusion criteria
    - Males and females between 18 and 85 years of age, inclusive, at screening.
    - Body mass index <35 kg/m^2.
    - Diagnosed with HCM per the following criteria:
    a. Has LV hypertrophy and non-dilated LV chamber in the absence of other cardiac disease and
    b. Has an end-diastolic LV wall thickness as measured by the echocardiography core laboratory of:
    • ≥15 mm in one or more myocardial segments OR
    • ≥13 mm in one or more wall segments and a known-disease-causing gene mutation or positive family history of HCM
    - Has resting LVOT-G ≥30 mmHg and post-Valsalva LVOT-G ≥50 mmHg during screening as determined by the echocardiography core laboratory
    - LVEF ≥60% at screening as determined by the echocardiography core laboratory.
    - New York Heart Association (NYHA) Functional Class II or III at screening
    - Hemoglobin ≥10 g/dL at screening.
    - Respiratory exchange ratio (RER) ≥1.05 and pVO2 <80% predicted on the screening CPET per the core laboratory.
    - Patients on beta-blockers, verapamil, diltiazem, or disopyramide should have been on a stable doses for >6 weeks prior to randomization and anticipate remaining on the same medication regimen during the trial. Patients treated with disopyramide must also be concomitantly treated with a beta blocker and/or calcium channel blocker.
    • Hombres y mujeres de entre 18 y 85 años de edad, inclusive, en la selección.
    • Índice de masa corporal <35 kg/m2.
    •Diagnóstico de MH según los criterios siguientes:
     -hipertrofia del VI y cavidad del VI no dilatada en ausencia de otra cardiopatía y
     -grosor de la pared telediastólica del VI, según lo determinado por el laboratorio central de la ecocardiografía, de:
    ≥15 mm en uno o más de los segmentos miocárdicos O BIEN
    ≥13 mm en uno o más de los segmentos parietales y una mutación genética conocida causante de la enfermedad o antecedentes familiares positivos de MH.

    •GIVI en reposo ≥30 mm Hg y GIVI posterior a la maniobra de Valsalva ≥50 mm Hg durante la selección, según lo determinado por el laboratorio central de la ecocardiografía.
    •FEVI ≥60 % en la selección, según lo determinado por el laboratorio central de la ecocardiografía.
    •Clase funcional II o III según la NYHA en la selección.
    •Hemoglobina ≥10 g/dl en la selección.
    •Cociente de intercambio gaseoso (CIG) ≥1,05 y pVO2 <80 % según lo previsto en la PECP de la selección y determinado por el laboratorio central.
    •Los pacientes que reciban tratamiento con betabloqueantes, verapamilo, diltiazem o disopiramida deben haber estado tomando dosis estables durante >6 semanas antes de la aleatorización y tener previsto continuar con la misma pauta farmacológica durante el ensayo. Los pacientes tratados con disopiramida también se deben tratar al mismo tiempo con un betabloqueante y/o un antagonista del calcio.
    E.4Principal exclusion criteria
    - Known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy that mimics oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis).
    - Significant valvular heart disease (per investigator judgment).
    a) Moderate-severe valvular aortic stenosis.
    b) Moderate-severe mitral regurgitation not due to systolic anterior motion of the mitral valve.
    - History of LV systolic dysfunction (LVEF <45%) or stress cardiomyopathy at any time during their clinical course.
    - Inability to exercise on a treadmill or bicycle (eg, orthopedic limitations).
    - Has been treated with septal reduction therapy (surgical myectomy or percutaneous alcohol septal ablation) or has plans for either treatment during the trial period.
    - Documented paroxysmal atrial fibrillation during the screening period.
    - Paroxysmal or permanent atrial fibrillation requiring rhythm restoring treatment (eg, direct-current cardioversion, atrial fibrillation ablation procedure, or antiarrhythmic therapy) ≤6 months prior to screening. (This exclusion does not apply if atrial fibrillation has been treated with anticoagulation and adequately rate-controlled for >6 months.)
    - History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening.
    - Has received prior treatment with CK-3773274 or mavacamten.
    Exclusion Criteria for CMR Sub-study
    - Inability to tolerate CMR.
    - Has an implantable cardioverter-defibrillator (ICD).
    - Has a cardiac pacemaker.
    •Tesaurismosis, trastorno genético o trastorno infiltrante, confirmado o que se sospecha, causante de hipertrofia cardiaca que imita la MHO (p. ej., síndrome de Noonan, enfermedad de Fabry o amiloidosis).
    •Valvulopatía significativa (según el criterio del investigador).
     - Estenosis aórtica valvular de moderada a grave.
     - Regurgitación mitral de moderada a grave que no se debe al movimiento sistólico en sentido anterior de la válvula mitral.
    •Antecedentes de disfunción sistólica del VI (FEVI <45 %) o miocardiopatía de esfuerzo en cualquier momento durante la evolución clínica.
    •Incapacidad para realizar ejercicio en una cinta sin fin o una bicicleta (p. ej., por limitaciones ortopédicas).
    •Haber recibido tratamiento con una terapia de reducción del tabique (miectomía quirúrgica o ablación septal percutánea con alcohol) o tener previsto someterse a uno de estos tratamientos durante el periodo del ensayo.
    •Fibrilación auricular paroxística documentada durante el periodo de selección.
    •Fibrilación auricular paroxística o permanente que requiere un tratamiento restaurador del ritmo (p. ej., cardioversión con corriente directa, procedimiento de ablación de la fibrilación auricular o terapia antiarrítmica) ≤6 meses antes de la selección. (Este criterio de exclusión no procede si la fibrilación auricular se ha tratado con anticoagulación y la frecuencia se ha controlado adecuadamente durante >6 meses.)
    •Antecedentes de síncope o taquiarritmia ventricular sostenida al realizar esfuerzo durante los 6 meses anteriores a la selección.
    •Haber recibido tratamiento previo con CK­3773274 o mavacamten.
    Criterios de exclusión para el subestudio de RMC
    •Incapacidad para tolerar la RMC.
    •Tener un cardiodesfibrilador implantable (DCI).
    •Tener un marcapasos cardiaco.
    E.5 End points
    E.5.1Primary end point(s)
    • Change in peak oxygen uptake (pVO2) by cardiopulmonary exercise testing (CPET)
    •Cambio, desde el inicio hasta la semana 24, en el consumo máximo de oxígeno (pVO2) medido mediante una prueba de esfuerzo cardiopulmonar (PECP)
    E.5.1.1Timepoint(s) of evaluation of this end point
    from baseline to Week 24
    desde el inicio hasta la semana 24
    E.5.2Secondary end point(s)
    • Change in Kansas City Cardiomyopathy Questionnaire – Clinical Summary Score (KCCQ-CSS)
    • Proportion of patients with ≥1 class improvement in NYHA Functional Class
    • Change in post-Valsalva LVOT-G
    • Proportion of patients with post-Valsalva LVOT-G <30 mmHg
    • Change in total workload during CPET

    Safety
    • Incidence of reported major adverse cardiac events (cardiovascular [CV] death, cardiac arrest, non-fatal stroke, non-fatal myocardial infarction, CV hospitalization)
    • Incidence of new onset persistent atrial fibrillation
    • Incidence of appropriate implantable cardiac defibrillator (ICD) discharges and aborted sudden cardiac death
    • Incidence of left ventricular ejection fraction (LVEF) <50%
    • Incidence of treatment emergent adverse events
    • Cambio en la puntuación resumida clínica del cuestionario de miocardiopatía de Kansas City (Kansas City Cardiomyopathy Questionnaire – Clinical Summary Score, KCCQ-CSS)
    • Proporción de pacientes con una mejoría de clase ≥1 en la clasificación funcional de la NYHA
    • Cambio en el GIVI después de realizar la maniobra de Valsalva
    • Proporción de pacientes con un GIVI posterior a la maniobra de Valsalva <30 mm Hg
    • Cambio en la carga de trabajo total durante la PECP
    E.5.2.1Timepoint(s) of evaluation of this end point
    KCCQ-CSS - baseline to Week 12 and Week 24
    NYHA Functional Class -baseline to Week 12 and Week 24
    Change in post-Valsalva LVOT-G - baseline to Week 12 and Week 24
    Proportion of patients with post-Valsava LVOT-G <30 mmHg - Week 12 and Week 24
    Total workload during CPET - baseline to Week 24
    Safety - Throughout the study
    KCCQ-CSS -desde el inicio hasta la semana 12 y la semana 24
    clasificación funcional de la NYHA, desde el inicio hasta la semana 12 y la semana 24
    Cambio en el GIVI después de realizar la maniobra de Valsalva_desde el inicio hasta la semana 12 y la semana 24
    Proporción de pacientes con un GIVI posterior a la maniobra de Valsalva <30 mm Hg -la semana 12 y la semana 24
    Cambio en la carga de trabajo total durante la PECP- desde el inicio hasta la semana 24
    Seguridad - A lo largo del estudio
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA45
    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
    China
    Israel
    United States
    Czechia
    Denmark
    France
    Germany
    Hungary
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months8
    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: 189
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 81
    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 state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 157
    F.4.2.2In the whole clinical trial 270
    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)
    Subjects who complete the Week 24 visit in CY 6031 will be offered the
    opportunity to participate in the open-label extension study CY 6022.
    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 Decision2022-04-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-04-25
    P. End of Trial
    P.End of Trial StatusOngoing
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