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    Summary
    EudraCT Number:2015-004402-42
    Sponsor's Protocol Code Number:HCMRanIT001
    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:2021-09-09
    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 number2015-004402-42
    A.3Full title of the trial
    A pilot study assessing the effects of Ranolazine on coronary microvascular dysfunction in patients with hypertrophic cardiomyopathy
    A pilot study assessing the effects of Ranolazine on coronary microvascular dysfunction in patients with hypertrophic cardiomyopathy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A pilot study assessing the effects of Ranolazine on small heart vessels dysfunction in patients with hypertrophic cardiomyopathy
    Studio pilota per valutare l’effetto di ranolazina sulla disfunzione microvascolare coronarica in pazienti affetti da cardiomiopatia ipertrofica
    A.3.2Name or abbreviated title of the trial where available
    Ranolazine microvascular dysfunction HCM
    Ranolazina nella disfunzione microvascolare in HCM
    A.4.1Sponsor's protocol code numberHCMRanIT001
    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 SponsorOSPEDALE SAN RAFFAELE
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    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 organisationOSPEDALE SAN RAFFAELE
    B.5.2Functional name of contact pointUfficio Ricerche Cliniche
    B.5.3 Address:
    B.5.3.1Street AddressVIA OLGETTINA 60
    B.5.3.2Town/ cityMilano
    B.5.3.3Post code20100
    B.5.3.4CountryItaly
    B.5.4Telephone number0226432191
    B.5.5Fax number0226432343
    B.5.6E-mailriva.elisabetta@hsr.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.2.1.1.1Trade name RANEXA - 750 MG - COMPRESSA A RILASCIO PROLUNGATO- USO ORALE - BLISTER (PVC/PVDC/ALLUMINIO) 60 COMPRESSE
    D.2.1.1.2Name of the Marketing Authorisation holderMENARINI INTERNATIONAL OPERATIONS LUXEMBOURG S.A.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameRanolazina Ranexa
    D.3.2Product code [C01EB18]
    D.3.4Pharmaceutical form Prolonged-release tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 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 primaria
    E.1.1.1Medical condition in easily understood language
    Inherited increase of the thickness of the left ventricular wall
    Aumento dello spessore delle pareti cardiache di origine congenita
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10020204
    E.1.2Term HOCM Hypertrophic obstructive cardiomyopathy
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10020203
    E.1.2Term HOCM
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10020876
    E.1.2Term Hypertrophic obstructive 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 demonstrate an increase of near maximal hyperaemic myocardial blood flow (MBF ml/min/g) after treatment with ranolazine. Measurement of myocardial perfusion with 13N-ammonia and positron emission tomography; assessment of hyperaemic Myocardial Blood Flow (MBF) following i.v. dipyridamole (0.56 mg/Kg in 4 mins).
    dimostrare un aumento del flusso miocardico iperemico massimale (MBF) (ml/min/g) dopo trattamento con Ranolazina. Misurazione della perfusione miocardica con PET 13N-ammoniaca; valutazione del flusso iperemico miocardico dopo infusione di dipiridamolo (0.56 mg/Kg in 4 minuti).
    E.2.2Secondary objectives of the trial
    To demonstrate an increase of Coronary Flow Reserve (hyperaemic MBF /resting MBF = CFR). A decrease of baseline coronary resistance (Mean Arterial Pressure rest/ MBF rest) and of minimal (dipyridamole) coronary resistance (Mean arterial Pressure hyperemia/ MBFhyperemia)
    dimostrare un aumento della riserva coronarica di flusso (CFR= MBF iperemico/MBF basale).
    Dimostrare una riduzione delle resistenze coronariche basali (pressione arteriosa media basale/MBF basale) e delle resistenze coronariche durante massima vasodilatazione con dipiridamolo (pressione arteriosa media in iperemia/MBF in iperemia).
    Valutazione della safety per mezzo di :
    Alterazioni nell’elettrocardiogramma di superficie a 12 derivazioni comprendenti la valutazione degli intervalli RR QT JT e del QRS in V2 V3.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male and female gender.
    2. Patients who fulfil conventional echocardiographic criteria for the diagnosis of HCM: maximum LV wall thickness = 15 mm;
    3. Patients aged > 18 years and < 80 years;
    4. Absence of severe resting LV outflow tract obstruction (peak gradient = 50 mmHg);
    5. Sinus rhythm; accepted isolated Supraventricular and Ventricular Premature Beats (VPB);
    6. Females of childbearing potential must be using highly effective contraceptive precautions such as implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence or vasectomised partner);
    7. Females of childbearing potential or within two years from the menopause must have a negative urine pregnancy test;
    8. Ability to give written informed consent prior to enrolment into the study;
    Entrambe i sessi
    Pazienti che ottemperano I criteri ecocardiografici convenzionali di HCM: max spessore parete ventricolare sinistra = 15 mm;
    Eta’ > 18 anni e < 80 anni;
    Assenza di grave ostruzione del tratto di efflusso ventricolare sinistro a riposo (gradient di picco = 50 mmHg);
    Ritmo sinusale ; accettati isolate battiti prematuri ventricolari e sopraventricolari;
    Donne in eta’ fertile che usano mezzi contraccettivi di comprovata efficacia o con partner stabile vasectomizzato;
    Donne in eta’ fertile o entro due anni dalla menopausa devono avere un test di gravidanza negativo;
    Capacita’ di fornire consenso informato scritto
    E.4Principal exclusion criteria
    1. severe resting LV outflow tract obstruction (peak gradient > 50 mmHg)
    2. Females of childbearing potential not using highly effective contraception;
    3. Presence of known coronary artery disease (CAD);
    4. Presence of Chronic Obstructive Airways Disease;
    5. Asthma;
    6. Other causes of microvascular dysfunction including long-standing history of arterial hypertension, diabetes, uncontrolled dyslipidemia;
    7. Body mass index >32 kg/m2; < 17 kg/m2
    8. Overt LV systolic dysfunction with end-stage progression (LV-EF <50%);
    9. Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazol, posaconazol, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone);
    10. Patients treated with sotalol, dronedarone, class I antiarrhythmics or other QT-prolonging drugs; stable treatment with amiodarone is permitted;
    11. Patients with QTc (Bazett’s formula) at baseline = 450 ms males; = 470 msec females
    12. Any clinically relevant haematological or biochemical abnormality on routine screening, according to Investigator’s judgment;
    13. Severe concurrent pathology, including terminal illness (cancer, AIDS, etc.);
    14. Severe renal impairment defined as GFR < 29 mL/min/1.73 m2 or creatinine level > 2.5 mg/dL or BUN >60 mg/dL;
    15. Moderate or severe hepatic impairment or hepatic insufficiency defined as SGOT or SGPT > 2 times greater than upper limit of normal of the local laboratory or total serum bilirubin > 1.5 times greater than normal upper limit of the local laboratory;
    16. Dementia, psychosis, alcoholism (>350 g ethanol/week) or chronic abuse of medicaments, drugs or psychoactive substances;
    17. Claustrophobia;
    18. Females who are pregnant or lactating;
    19. Conditions which in the Investigator’s opinion may interfere with the study’s execution or due to which the patient should not participate for safety reasons;
    20. Risk of poor patient cooperation;
    21. Participation into a clinical study = 2 months before enrolment;
    22. Inability or unwillingness to issue the informed consent;
    23. Concomitant use of >20 mg daily dose of Simvastatin during the study (in case of patients taking simvastatin > 20 mg daily, the switch to other statins not metabolized by the CYP3A4 could be considered);
    24. Concomitant use of Atorvastatin (>80 mg daily);
    25. Concomitant use of >1000 mg daily dose of metformin during the study.
    Grave ostruzione del tratto di efflusso ventricolare sinistro a riposo (gradiente di picco = 50 mmHg);
    Donne in eta’ fertile che non usano mezzi contraccettivi di comprovata efficacia;
    Presenza di coronaropatia nota;
    Presenza di broncopneumopatia ostruttiva cronica;
    Asma;
    Altre cause di disfunzione microvascolare quali ipertensione. diabete, dislipidemia non controllata;
    Body mass index >32 kg/m2; < 17 kg/m2
    Disfunzione sistolica ventricolare sinistra (LV-EF <50%);
    Assunzione concomitante di potenti inibitori dell’enzima CYP3A4 (itraconazolo, ketoconazolo, voriconazolo, posaconazolo, inibitori della proteasi HIV, claritromycina, telithromycina, nefazodone);
    Pazienti trattati con sotalolo dronedarone, antiaritmici di classe I o altri farmaci che prolungano l’intervallo QT; trattamento stabilizzato con amiodarone e’ consentito.
    QTc (Bazett formula) basale = 450 ms maschi;>470 msec femmine
    Anomalie ematologiche o biochimiche;
    Patologie gravi associate quali cancro, AIDS etc.
    Insufficienza renale grave GFR < 29 mL/min/1.73 m2 o creatinina > 2.5 mg/dL or BUN >60 mg/dL;
    Insufficienza epatica SGOT or SGPT > 2 volte il limite superiore di normalita’ ,bilirubina serica totale > 1.5 volte il limite superiore di normalita’
    Demenza, psicosi, alcolismo, abuso di sostanze psicotrope;
    Claustrofobia;
    Donne gravide o in allattamento;
    Partecipazione ad un trial clinico = 2 mesi prima dell’arruolamento;
    Incapacita’ di dare il consenso informato;
    Uso concomitante di >20 mg die Simvastatin;
    Uso concomitante di Atorvastatin (>80 mg die);
    Uso concomitante di metformin >1000 mg die.
    E.5 End points
    E.5.1Primary end point(s)
    Hyperemic myocardial blood flow (ml/min/g) before and after treatment with ranolazine
    Misurazione della perfusione miocardica con PET 13N-ammoniaca per identificare un aumento del flusso miocardico iperemico massimale (MBF) (ml/min/g) dopo trattamento con Ranolazina
    E.5.1.1Timepoint(s) of evaluation of this end point
    Fourteen days before titration and 120 days after active treatment with Ranolazine
    14 giorni prima dell’inizio della fase di titolazione e dopo 120 giorni di trattamento attivo
    E.5.2Secondary end point(s)
    increase of Coronary Flow Reserve (hyperaemic MBF /resting MBF = CFR). A decrease of baseline coronary resistance (Mean Arterial Pressure rest/ MBF rest) and of minimal (dipyridamole) coronary resistance (Mean arterial Pressure hyperemia/ MBFhyperemia)
    aumento della riserva coronarica di flusso (CFR= MBF iperemico/MBF basale).
    riduzione delle resistenze coronariche basali (pressione arteriosa media basale/MBF basale) e delle resistenze coronariche durante massima vasodilatazione con dipiridamolo (pressione arteriosa media in iperemia/MBF in iperemia).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Fourteen days before titration and 120 days after active treatment with Ranolazine
    14 giorni prima dell’inizio della fase di titolazione e dopo 120 giorni di trattamento attivo
    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 Yes
    E.6.13.1Other scope of the trial description
    Physiopathologic mechanism of efficacy
    meccanismo fisiopatologico di efficacia
    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 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 Yes
    E.8.1.7.1Other trial design description
    Studio pilota unico gruppo pre e post trattamento
    Pilot study one group pre post treatment.
    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 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 concerned2
    E.8.5The trial involves multiple Member States No
    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 Information not present in EudraCT
    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
    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 months6
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days1
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 24
    F.4.2.2In the whole clinical trial 24
    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)
    Return to GP ongoing therapy
    Ritorno al medico curante con terapia usuale
    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 Decision2016-09-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-10-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-03-06
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