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    Summary
    EudraCT Number:2019-001491-11
    Sponsor's Protocol Code Number:EV01
    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:2021-05-24
    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 number2019-001491-11
    A.3Full title of the trial
    Phase IV study for efficacy and safety of Evolocumab added to Ezetimibe (Standard of Care) in high cardiovascular risk haemodialized statin intolerant patients with hypercholesterolemia.
    Studio di Fase IV per valutare l’efficacia e la sicurezza di Evolocumab aggiunta alla terapia standard di Ezetimibe in pazienti ad alto rischio cardiovascolare con ipercolesterolemia ed emodializzati intolleranti alle statine
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of Evoluocumab added Standard of Care in high cardiovascular risk haemodialized statin intolerant patients with hypercholesterolemia.
    Efficacia e sicurezza di Evolocumab in aggiunta alla terapia standard in pazienti ad alto rischio cardiovascolare con ipercolesterolemia ed emodializzati intolleranti alle statine
    A.3.2Name or abbreviated title of the trial where available
    EV01
    EV01
    A.4.1Sponsor's protocol code numberEV01
    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 SponsorIRCCS SAN RAFFAELE PISANA GESTITO DA SAN RAFFAELE ROMA SRL
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIRCCS San Raffaele Pisana
    B.5.2Functional name of contact pointDirezione scientifica
    B.5.3 Address:
    B.5.3.1Street AddressVia di Val Cannuta 247
    B.5.3.2Town/ cityRoma
    B.5.3.3Post code00166
    B.5.3.4CountryItaly
    B.5.4Telephone number0652253405
    B.5.6E-mailastrid.vanrijn@sanraffaele.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 REPATHA - 140 MG- SOLUZIONE INIETTABILE- USO SOTTOCUTANEO- SIRINGA PRERIEMPITA (VETRO) (SURECLICK) 1 ML- 1 PENNA PRERIEMPITA
    D.2.1.1.2Name of the Marketing Authorisation holderAMGEN EUROPE B.V.
    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 nameREPATHA
    D.3.2Product code [C10AX13]
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEVOLOCUMAB
    D.3.9.1CAS number 1256937-27-5
    D.3.9.2Current sponsor codeEVOLOCUMAB
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number140
    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) Yes
    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) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    High cardiovascular risk haemodialized statin intolerant patients with hypercholesterolemia.
    pazienti ad alto rischio cardiovascolare con ipercolesterolemia, intolleranti alle statine ed emodializzati
    E.1.1.1Medical condition in easily understood language
    Haemodialized patients with high cardiovascular risk with sustained cholesterol levels and intolerant to statins.
    Pazienti emodializzati ad alto rischio cardiovascolare con alti livelli di colesterolo e intolleranti alle statine
    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 HLGT
    E.1.2Classification code 10013317
    E.1.2Term Lipid metabolism disorders
    E.1.2System Organ Class 10027433 - Metabolism and nutrition disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level SOC
    E.1.2Classification code 10007541
    E.1.2Term Cardiac disorders
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level SOC
    E.1.2Classification code 10047065
    E.1.2Term Vascular disorders
    E.1.2System Organ Class 10047065 - Vascular 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 endpoint of this trial is to determine whether the treatment with a new therapeutic strategy (Evolocumab + Ezetimibe) is non-inferior to Ezetimibe alone, in reducing the LDL-C percentage from baseline to week 24, considering an ITT approach, in high cardiovascular risk statin-intolerant patients with hypercholesterolemia and ESRD, receiving maintenance haemodialysis.
    L'obiettivo primario di questo studio è determinare se il trattamento con una nuova strategia terapeutica che prevede l’aggiunta di Evolocumaballa terapia standard a base di Ezetimibe non sia inferiore al solo trattamento standard (Ezetimibe)nel ridurre la percentuale di colesterolo LDL dal basale T0 alla settimana 24 (T24), considerando un approccio ITT, in pazienti con altro rischio cardiovascolare, intolleranti alle statine, con ipercolesterolemia ed insufficienza renale e sottoposti a emodialisi di mantenimento.
    E.2.2Secondary objectives of the trial
    To assess whether the new treatment with Evolocumab+Ezetimibe is non-inferior to usual therapy with Ezetimibe alone in terms of LDL-C reduction, comparing baseline measures versus 4, 12, 24 weeks measures;
    To evaluate the changes of other lipid parameters (HDL cholesterol, non-HDL cholesterol, triglycerides) from baseline to week 24 (ITT/on-treatment analysis);
    To evaluate the percentage of patients that reach the LDL-C < 70 mg/dL target at week 24 (ITT/on-treatment analysis);
    To evaluate the tolerability of Evolocumab, analyzing adverse events reports and laboratory values from the time of signed informed consent until the end of the study, and the hemodynamic stability during haemodialysis.
    Valutare se l’aggiunta di Evolocumabal trattamento standard di Ezetimibe sia non inferiore alla normale terapia con il solo Ezetimibe in termini di riduzione del colesterolo LDL, confrontando le misure di riferimento (baseline – T0) rispetto alle misure prese a 4, 12, 24
    settimane.
    Valutare i cambiamenti di altri parametri lipidici (colesterolo HDL, colesterolo non HDL,
    trigliceridi) dal basale alla settimana 24;
    Valutare la percentuale di pazienti che raggiungono l'obiettivo LDL-C<70 mg/dL alla
    settimana 24.
    Valutare la tollerabilità di Evolocumab, in aggiunta alla terapia standard, analizzando il
    profilo di sicurezza tramite l’analisi degli eventi avversi edei valori di laboratorio, nonché
    della stabilità emodinamica durante l'emodialisi, durante tutta la durata dello studio.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients will be included in the study if all of the following criteria are met:
    - Age = 18; both genders.
    - High cardiovascular risk patients defined as: patients with established coronary heart disease (CHD), OR patients with CHD risk equivalents (ischemic stroke, peripheral artery disease, diabetes mellitus plus at least 2 additional risk factors);
    - Statin-intolerant patients with not adequately controlled LDL-C levels (=70 mg/dL)
    - Patients with uremia on periodic haemodialysis treatment.
    I pazienti saranno inclusi nello studio se tutti i seguenti criteri sono soddisfatti:
    - Età = 18; entrambi i sessi.
    - Pazienti con alto rischio cardiovascolare definiti come: pazienti con malattia coronarica cardiaca accertata (CHD), pazienti con OR con valori di rischio CHD (ictus ischemico, malattia delle arterie periferiche, diabete mellito più almeno 2 fattori di rischio aggiuntivi);
    - Pazienti intolleranti alle statine con livelli di LDL-C adeguatamente controllati (=70 mg/dL)
    - Pazienti con uremia su trattamento emodialitico periodico.
    E.4Principal exclusion criteria
    - LDL-C <70 mg/dL
    - Age < 18 years.
    - LDL-C <70 mg/dL;
    - Età inferiore ai 18 anni.
    E.5 End points
    E.5.1Primary end point(s)
    Observing in high cardiovascular risk statin-intolerant patients with hypercholesterolemia and ESRD, receiving maintenance haemodialysis, a LDL-C level reduction of at least 20 mg/dL
    L’endpoint primario è rappresentato, nella popolazione in studio, da una riduzione del livello di
    colesterolo LDLdi almeno 20 mg/dLmisurato mediante ultracentrifugazione
    E.5.1.1Timepoint(s) of evaluation of this end point
    The survey will take place at the 24th week
    La rilevazione avverrà alla 24 settimana
    E.5.2Secondary end point(s)
    - To observe a LDL-C reduction comparing baseline measures versus 4, 12, 24 weeks measures, considering the new treatment with Evolocumab+Ezetimibe versus Ezetimibe alone;
    - To describe the changes of other lipid parameters (HDL cholesterol, non-HDL cholesterol, triglycerides) from baseline to week 24 (ITT/on-treatment analysis);
    - To observe the percentage of patients that reach the LDL-C < 70 mg/dL target at week 24 (ITT/on-treatment analysis).
    - To evaluate the tolerability of Evolocumab, analyzing adverse events reports and laboratory values from the time of signed informed consent until the end of the study, and the hemodynamic stability during haemodialysis.
    - Riduzione del valore di LDL-C, confrontando le misure basali rispetto alle misure a 4, 12, 24
    settimane, confrontando il nuovo trattamento con Evolocumab +Ezetimibe rispetto a
    Ezetimibe+ Placebo;
    - Cambiamenti su altri parametri lipidici (colesterolo HDL, colesterolo non HDL, trigliceridi)
    dal basale alla settimana 24 (analisi ITT/OT);
    - Percentuale di pazienti che raggiungono il target LDL-C<70 mg/dL alla settimana 24 (analisi
    ITT/OT).
    - Tollerabilità di Evolocumab, in termini di variazione percentuale e analisi dei tassi di eventi
    avversi e valori di laboratorio, nonché della stabilità emodinamica durante l'emodialisi,
    durante tutta la durata dello studio.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The surveys will be carried out at 4,12 and 24 weeks
    Le rilevazione verranno effettuate alla 4, 12 e 24 settimana
    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 No
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States 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
    last visit of the last subject: LVLS
    ultima visita dell'ultimo soggetto: LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days19
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days19
    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: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 50
    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)
    At the end of the study the patients will continue to be followed in the usual procedures of clinical practice
    Alla fine dello studio i pazienti coontinueranno ad essere seguiti nelle abituali procedure della pratica clinica.
    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 Decision2020-07-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-10-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-03-14
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