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    Summary
    EudraCT Number:2011-000805-27
    Sponsor's Protocol Code Number:MEIN/10/Ran-Did/001
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-05-10
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2011-000805-27
    A.3Full title of the trial
    Effect of Ranolazine in Heart Failure Patients with Preserved Ejection Fraction
    Efecto de la ranolazina en pacientes con insuficiencia cardiaca y fracción de eyección preservada
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effect of Ranolazine in Heart Failure Patients
    Efecto de la ranolazina en pacientes con insuficiencia cardiaca
    A.3.2Name or abbreviated title of the trial where available
    ERIPE
    ERIPE
    A.4.1Sponsor's protocol code numberMEIN/10/Ran-Did/001
    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 SponsorMenarini International Operations Luxembourg S.A., Avenue de la Gare, 1611 Luxembourg, Luxembourg
    B.1.3.4CountryItaly
    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 supportMenarini International Operations Luxembourg S.A.
    B.4.2CountryLuxembourg
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationA. Menarini Farmaceutica Internazionale S.R.L.
    B.5.2Functional name of contact pointDonatella Bemporad
    B.5.3 Address:
    B.5.3.1Street AddressVia Sette Santi 3
    B.5.3.2Town/ cityFlorence
    B.5.3.3Post code50131
    B.5.3.4CountryItaly
    B.5.4Telephone number+390555680685
    B.5.5Fax number+390555680484
    B.5.6E-mailDBemporad@menarini.it
    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 Yes
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.4Pharmaceutical form Prolonged-release 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 INNRANOLAZINE
    D.3.9.1CAS number 95635-55-5
    D.3.9.2Current sponsor codeI 293
    D.3.9.4EV Substance CodeSUB10259MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number500 to 1000
    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
    Heart failure patients with preserved ejection fraction (HFpEF)
    Pacientes con insuficiencia cardiaca y fracción de eyección preservada
    E.1.1.1Medical condition in easily understood language
    Heart failure
    insuficiencia cardiaca
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level HLGT
    E.1.2Classification code 10019280
    E.1.2Term Heart failures
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to demonstrate that ranolazine treatment results in a placebo corrected improvement in the 6-minute walk test (6MWT) after 28 weeks of treatment
    El objetivo principal es demostrar que el tratamiento con ranolazina resulta en una mejora corregida con placebo en la prueba de marcha de seis minutos (PM6M) tras 28 semanas de tratamiento
    E.2.2Secondary objectives of the trial
    Mitral flow velocity to mitral annular velocity ratio (E/E?) from baseline to 6 months
    Mitral flow: maximum velocity during early diastole (VmaxE); maximal velocity during atrial contraction (VmaxA); deceleration time of E wave; isovolumetric relaxation time (IVRT)
    Tricuspidal regurgitation
    Vmax of septal and lateral E? measured by Tissue Doppler Echocardiography (TDE)
    2D strain evaluation: longitudinal systolic strain, LV twist, global diastolic longitudinal strain rate during isovolumic relaxation (IVR) and early diastole/untwisting rate
    Arterial elastance (LV end systolic pressure/stroke volume) and LV end systolic elastance (LV end systolic pressure/LV end systolic volume)
    Relación entre la velocidad de flujo mitral y la velocidad del anillo mitral (E/E?) desde el valor inicial hasta los 6 meses
    Flujo mitral: velocidad máxima durante la diástole prematura (VmaxE); velocidad máxima durante la contracción auricular (VmaxA); el tiempo de desaceleración de la onda E, tiempo de relajación isovolumétrica (TRIV)
    Regurgitación tricuspídea Vmax del gradiente sistólico ventricular derecho-auricular derecho
    Vmax de E' septal y lateral medida por ecocardiografía Doppler de tejidos (EDT)
    Valoración de la tensión en 2D: tensión sistólica longitudinal, torsión VI, tasa de tensión longitudinal diastólica global, durante la relajación isovolumétrica (RIV) y la tasa de diástole prematura/fin de la torsión
    Elastancia arterial (presión sistólica final del ventrículo izquierdo/volumen sistólico) y elastancia sistólica final del ventrículo izquierdo (presión sistólica final del ventrículo izquierdo/volumen sistólico final del ventrículo izquierdo)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female between the ages of 40 to 85 years, inclusive
    2. Heart failure with preserved EF defined by the following:
    a. Signs or symptoms of HF (previous documented hospitalization for HF, decompensation in the last 12 months, or exertional dyspnea or fatigue, New York Heart Association [NYHA] Class II-IV with or without clinical signs of HF)
    b. LVEF > 45% measured by echocardiogram
    c. NT-ProBNP > 200 pg/ml or BNP > 80 pg/ml
    d. Evidence of LV diastolic dysfunction or increased LV filling pressure documented in the last month and defined by the following:
    ? LV end diastolic pressure > 16 mmHg
    ? or E/E? > 15 (septal annular velocity)
    ? or E/E? between 8 and 15 and at least one of the following:
    ? Plasma brain natriuretic peptide (BNP) > 150 pg/ ml or plasma N terminal pro b-type natriuretic peptide (NT proBNP) > 450 pg/ml
    ? Ratio of early (E) to late (A) mitral valve flow velocity (E/A) < 0.5 and mitral flow deceleration time (DT E) > 280 ms
    ? LV atrial area > 25 cm² (apical 4 chamber)
    ? LV posterior wall thickness > 12 mm
    e. Sinus rhythm
    3. Written informed consent
    4. 6MWT distance ? 450 meters and ? 100 meters at screening
    1. Hombre o mujer entre 40 y 85 años, inclusive
    2. Insuficiencia cardiaca con FE preservada definida por lo siguiente:
    a. Signos o síntomas de IC (hospitalizaciones anteriores documentadas por IC, descompensación en los últimos 12 meses o disnea o fatiga de esfuerzo, clase II-IV según la New York Heart Association [NYHA, Asociación Cardiológica de Nueva York] con o sin signos clínicos de IC).
    b. FEVI > 45% medida mediante ecocardiograma
    c. NT-ProBNP > 200 pg/ml o BNP > 80 pg/ml
    d. Evidencia de disfunción diastólica VI o aumento de la presión de llenado VI documentada en el último mes y definida por lo siguiente:
    ? Presión diastólica VI final > 16 mmHg
    ? o E/E? > 15 (velocidad anular septal)
    ? o E/E? entre 8 y 15 y al menos uno de los siguientes:
    ? Péptido natriurético cerebral (BNP) plasmático > 150 pg/ ml o prohormona N-terminal del péptido natriurético cerebral plasmática (NT proBNP) > 450 pg/ml
    ? Relación entre la velocidad de flujo mitral prematuro (E) y tardío (A) (E/A) < 0,5 y tiempo de desaceleración del flujo mitral (TD E) > 280 ms
    ? Área auricular VI > 25 cm² (apical de 4 cámaras)
    ? Grosor de la pared posterior del VI > 12 mm
    e. Ritmo sinusal
    3. Consentimiento informado escrito
    4. Distancia en PM6M ? 450 metros y ? 100 metros en la selección
    E.4Principal exclusion criteria
    1. Unstable situation for acute acute coronary syndrome, or worsening angina in the last 3 months
    2. Unstable situation for acute heart failure in the last month
    3. Poor echogenicity
    4. Significant chronic lung disease (e.g., chronic obstructive pulmonary disease, asthma), prior hospitalization for acute exacerbation, home oxygen use, chronic inhaled or systemic steroid therapy
    5. Documented hypertrophic or restrictive cardiomyopathy
    6. Body mass index (BMI) ? 30 kg/m2
    7. Tricuspid Rigurgitation Max Velocity > 4m/s
    8. Previous Heart Failure hospitalization or decompensation, with documented LV Systolic Dysfunction (LVEF ? 45%)
    9. Sustained atrial fibrillation or flutter in the previous 3 months
    10. Change in cardiovascular medication during the last 4 weeks
    11. Change in diuretic medication during the last 2 weeks
    12. Revascularization within the last 3 months
    13. Second- or third-degree atrioventricular (AV) block
    14. Severe and uncontrolled hypertension stage 3 (systolic blood pressure > 180 mmHg or diastolic blood pressure > 100 mmHg)
    15. Significant valvular disease: moderate or severe mitral or aortic valve disease
    16. Severe renal impairment (creatinine clearance < 30 ml/min)
    17. Moderate or severe hepatic impairment (Child-Pugh Class A or Class B)
    18. Previous cardiac surgery
    19. Inability to perform the 6MWT
    20. 6MWT distance > 450 meters or < 100 meters at screening
    21. Screening and baseline 6-minute walk distance (6MWD) with >10% variability
    22. Stroke within the last 3 months
    23. Implantable pacemaker for chronotropic incompetence, cardioverter defibrillator, or LV assist device
    24. Prior heart transplantation
    25. Current treatment with potent inhibitors of CYP3A, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir
    26. Current treatment with CYP3A inducers, such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John?s wort
    27. Concomitant administration of Class Ia (e.g., quinidine) or Class III (e.g., dofetilide, sotalol) antiarrhythmics other than amiodarone
    28. Use of greater than 1000mg daily dose of metformin during the study
    29. Use of over 20 mg daily dose of simvastatin
    30. Prior treatment with ranolazine
    31. Hypersensitivity to the active substance or to any of the excipients
    32. Participation in another trial of an investigational drug or device within 30 days prior to screening
    33. Pregnant or breast-feeding
    34. Severe psychiatric disorders/neurological disorders
    35. Abuse of alcohol, analgesics, or psychotropic drugs
    36. Disabling or terminal illness
    37. Inability or unwillingness, in the Investigator?s opinion, to follow study procedures
    1. Situación inestable por síndrome coronario agudo o empeoramiento de la angina en los últimos 3 meses
    2. Situación inestable por insuficiencia cardiaca aguda en el último mes
    3. Mala ecogenicidad
    4. Enfermedad pulmonar crónica significativa (p. ej. enfermedad pulmonar obstructiva crónica o asma), hospitalizaciones anteriores por exacerbación aguda, uso de oxígeno domiciliario, terapia crónica con esteroides inhalados o sistémicos
    5. Miocardiopatía hipertrófica o restrictiva documentada
    6. Índice de masa corporal (IMC) ? 32 kg/m2
    7. Velocidad máxima de la regurgitación tricuspídea > 4 m/s
    8. Hospitalización previa por insuficiencia cardiaca o descompensación, con disfunción sistólica del VI documentada (FEVI ? 45%) ? 45%)
    9. Fibrilación auricular sostenida o aleteo en los 3 meses anteriores
    10. Cambio en la medicación cardiovascular durante las últimas 4 semanas
    11. Cambio en la medicación diurética durante las últimas 2 semanas
    12. Revascularización durante los últimos 3 meses
    13. Bloqueo atrioventricular (AV) de segundo o tercer grado
    14. Hipertensión en fase 3 grave y sin controlar (presión sanguínea sistólica > 180 mmHg o presión diastólica > 100 mmHg)
    15. Enfermedad valvular significativa: enfermedad de la válvula mitral o aórtica moderada o grave
    16. Insuficiencia renal grave (aclaramiento de creatinina < 30 ml/min)
    17. Insuficiencia hepática moderada o grave (Clase A o B de Child-Pugh)
    18. Cirugía cardiaca anterior
    19. Incapacidad para realizar la PM6M
    20. Distancia en PM6M > 450 metros o < 100 metros en la selección
    21. Distancia de marcha de 6 minutos (DM6M) en la selección y el valor inicial con una variabilidad > 10%
    22. Ictus durante los últimos 3 meses
    23. Marcapasos implantable por incompetencia cronotrópica, desfibrilador cardioversor o dispositivo de asistencia VI
    24. Transplante cardiaco anterior
    25. Tratamiento actual con inhibidores potentes de la CYP3A, como cetoconazol, itraconazol, claritromicina, nefazodona, nelfinavir, ritonavir, indinavir y saquinavir
    26. Tratamiento actual con inductores de la CYP3A, como rifampina, rifabutina, rifapentina, fenobarbital, fenitoina, carbamazepina e hierba de San Juan
    27. Administración concomitante de antiarrítmicos de clase Ia (como quinidina) o clase III (como dofetilida o sotalol) que no sean amiodarona
    28. Uso de una dosis diaria de más de 1000 mg de metformina durante el estudio
    29. El uso de dosis más de 20 mg diarios de simvastatina
    30. Tratamiento anterior con ranolazina
    31. Hipersensibilidad a la sustancia activa o a cualquiera de los excipientes
    32. Participación en otro ensayo con un fármaco o dispositivo en investigación en los 30 días anteriores a la selección
    33. Embarazo o lactancia
    34. Trastornos psiquiátricos o neurológicos graves
    35. Abuso de alcohol, analgésicos o drogas psicotrópicas
    36. Enfermedad incapacitante o terminal
    37. Incapacidad o negativa, a juicio del Investigador, de seguir los procedimientos del estudio
    E.5 End points
    E.5.1Primary end point(s)
    6-minute walk test
    Prueba de marcha de 6 minutos
    E.5.1.1Timepoint(s) of evaluation of this end point
    after 16 and 28 weeks
    después de 16 y 28 semanas
    E.5.2Secondary end point(s)
    Central blinded Echolab evaluation
    NT-proBNP(13)
    Quality of Life scale (Minnesota Living with HF Questionnaire)
    Electrocardiogram
    Safety assessments
    Centro de evaluación ciega Echolab
    NT-proBNP (13)
    Escala de Calidad de Vida (Minnesota Living with HF Cuestionario)
    electrocardiograma
    Las evaluaciones de seguridad
    E.5.2.1Timepoint(s) of evaluation of this end point
    after 16 and 28 weeks
    después de 16 y 28 semanas
    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 No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    LPLV
    LPLV
    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 months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    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: 120
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 120
    F.4.2.2In the whole clinical trial 120
    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)
    according to the clinical practice
    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 Decision2012-07-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-07-05
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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