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    Summary
    EudraCT Number:2012-003499-37
    Sponsor's Protocol Code Number:DSC/11/2357/44
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2012-12-19
    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 number2012-003499-37
    A.3Full title of the trial
    Long-term study evaluating the effect of Givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms.
    Studio a lungo termine volto alla valutazione dell'effetto di Givinostat in pazienti JAK2V617F positivi affetti da neoplasie mieloproliferative croniche.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Long-term study evaluating the effect of Givinostat in cMPN.
    Studio a lungo termine volto alla valutazione dell'effetto di Givinostat nelle sindromi mieloproliferative croniche.
    A.4.1Sponsor's protocol code numberDSC/11/2357/44
    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 SponsorITALFARMACO
    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 supportITALFARMACO S.p.A.
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationITALFARMACO S.p.A.
    B.5.2Functional name of contact pointClinical R&D Department
    B.5.3 Address:
    B.5.3.1Street AddressVia Dei Lavoratori, 54
    B.5.3.2Town/ cityCinisello Balsamo
    B.5.3.3Post code20092
    B.5.3.4CountryItaly
    B.5.4Telephone number0264432520
    B.5.5Fax number0264433554
    B.5.6E-mailt.delmuth@italfarmaco.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 nameGivinostat
    D.3.2Product code ITF2357
    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 INNGivinostat
    D.3.9.1CAS number 732302-99-7
    D.3.9.2Current sponsor codeITF2357
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 Yes
    D.3.11.13.1Other medicinal product typeinibitore dell'istone deacetilasi (HDAC)
    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 nameGivinostat
    D.3.2Product code ITF2357
    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 INNGivinostat
    D.3.9.1CAS number 732302-99-7
    D.3.9.2Current sponsor codeITF2357
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 Yes
    D.3.11.13.1Other medicinal product typeinibitore dell'istone deacetilasi (HDAC)
    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
    Chronic myeloproliferative neoplasms (cMPN).
    Neoplasia mieloproliferativa cronica (NMPc).
    E.1.1.1Medical condition in easily understood language
    JAK2V617F positive chronic myeloproliferative neoplasm including: Polycythemia Vera, Essential Trombocytemia, Primary Myelofibrosis, Post-PV Myelofibrosis, Post-ET Myelofibrosis.
    Neoplasie mieloproliferative croniche JAK2V617F positive inclusa: Policitemia Vera, Trombocitemia Essenziale, Mielofibrosi Primaria, Mielofibrosi Post-PV, Mielofibrosi Post-ET.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level HLT
    E.1.2Classification code 10028578
    E.1.2Term Myeloproliferative disorders (excl leukaemias)
    E.1.2System Organ Class 100000004851
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To determine the long term safety and tolerability of Givinostat in patients with cMPN following core protocols or compassionate use program; - To obtain information on the long term efficacy of Givinostat in patients with cMPN following core protocols or compassionate use program.
    - Valutare la sicurezza e la tollerabilità a lungo termine di Givinostat nei pazienti affetti da cMPN al termine di protocolli core o di un programma di uso compassionevole; - Ottenere informazioni sull’efficacia a lungo termine di Givinostat nei pazienti affetti da cMPN al termine protocolli core o di un programma di uso compassionevole.
    E.2.2Secondary objectives of the trial
    - To evaluate the effect of Givinostat on single parameters of the PV, ET and MF response criteria; - To evaluate the molecular response (JAK2 mutated allele burden) by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR); - To identify potential other markers predictive of clinical benefit of Givinostat (e.g. potential pharmacodynamic - PD - markers).
    - Valutare l’effetto di Givinostat sui singoli parametri che compongono i criteri di risposta nella PV, nella ET e nella MF. - Valutare la risposta molecolare (carico allelico di JAK2 mutato) mediante la Reazione a Catena della Polimerasi quantitativa e in Tempo Reale (qRT-PCR). - Identificare eventuali altri marcatori predittivi del beneficio clinico di Givinostat (come per esempio eventuali marcatori farmacodinamici (PD)).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients must have completed Givinostat treatment on at least one core study in cMPN (i.e. Study DSC/07/2357/28, Study DSC/08/2357/38 and/or any further core protocols in cMPN), or Patients must be participating in a compassionate use program with Givinostat; 2. Patients must be able to provide informed consent and be willing to sign an informed consent form; 3. Adult patients (age ≥ 18 years) of both genders with established diagnosis of JAK2 V617F positive cMPN according to the revised WHO criteria; 4. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status < 3; 5. Acceptable organ function within 7 days of initiating study drug; 6. Use of an effective means of contraception for women of childbearing potential and men with partners of childbearing potential; 7. Willingness and capability to comply with the requirements of the study.
    1. I pazienti devono aver completato il trattamento con Givinostat in almeno uno degli studi core condotti nelle cMPN (quali lo Studio DSC/07/2357/28, lo Studio DSC/08/2357/38 e/o qualsiasi futuro protocollo core nelle cMPN), o I pazienti devono essere in trattamento con Givinostat all’interno di un programma di uso compassionevole; 2. I pazienti devono essere in grado di fornire un consenso informato ed essere disposti a firmare un modulo di consenso informato; 3. Pazienti adulti (età ≥ 18 anni), di entrambi i generi, JAK2V617F positivi e con una diagnosi di cMPN stabilita in accordo ai criteri WHO rivisti; 4. I pazienti devono avere un Eastern Cooperative Oncology Group (ECOG) performance status &lt; 3; 5. Accettabile funzione degli organi nei 7 giorni precedenti l’inizio dello studio; 6. Utilizzo di un metodo anticoncezionale efficace per le donne in età fertile e gli uomini con partner in età fertile; 7. Disponibilità e capacità di seguire le procedure richieste dallo studio.
    E.4Principal exclusion criteria
    1. Active bacterial or mycotic infection requiring antimicrobial treatment; 2. Pregnancy or nursing; 3. A clinically significant QTc prolongation at baseline (e.g. repeated demonstration of a QTc interval > 450 ms); 4. Use of concomitant medications known to prolong the QTc interval; 5. Clinically significant cardiovascular disease including: - Uncontrolled hypertension, myocardial infarction, unstable angina within 6 months from study start; - New York Heart Association (NYHA) Grade II or greater congestive heart failure; - History of any cardiac arrhythmia requiring medication (irrespective of its severity); - A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome); (for a complete list refer to the protocol)
    1. Infezioni attive batteriche o micotiche che richiedono il trattamento con antimicrobici; 2. Gravidanza o allattamento; 3. Un prolungamento dell’intervallo QTc clinicamente rilevanti al basale (per esempio una dimostrazione ripetuta di QTc &gt; 450 msec); 4. Uso di farmaci concomitanti noti per prolungare l’intervallo QTc; 5. Patologie cardiovascolari clinicamente rilevanti, quali: - Ipertensione non controllata, infarto del miocardio, angina instabile nei 6 mesi precedenti l’inizio dello studio; - Scompenso cardiaco di grado 2 o superiore, secondo i criteri NYHA (New York Heart Association); - Storia di un qualsiasi tipo di aritmia cardiaca che ha richiesto un trattamento (indipendentemente dalla sua severità); - Una storia di ulteriori fattori di rischio della torsione di punta (per esempio infarto, ipocaliemia, storia familiare di sindrome del QTc lungo); (per l'elenco completo si veda il protocollo).
    E.5 End points
    E.5.1Primary end point(s)
    Long term safety and tolerability - Number of patients experiencing adverse events; - Type, incidence, and severity of treatment-related adverse events, graded according to Common Terminology Criteria for Adverse Events (CTCAE v. 4.03, 14th June 2010). Long term efficacy - For PV and ET, Complete response (CR) and partial response (PR) rate according to the revised clinico-haematological European LeukemiaNet (ELN) response criteria; - For MF, complete response, major response, moderate response and minor response rate according to European Myelofibrosis Network (EUMNET) response criteria.
    Sicurezza e tollerabilità a lungo termine - Numero di pazienti che hanno avuto eventi avversi; - Tipo, incidenza, e severità degli eventi avversi correlati al trattamento, con assegnazione del grado in accordo con i Criteri Comuni della Terminologia per gli Eventi Avversi (CTCAE v. 4.03, 14 Giugno 2010). Efficacia a lungo termine - Per la PV ed la ET, numero di Risposte Complete (CR) e Risposte Parziali (PR) definite in accordo a criteri di risposta clinico-ematologici rivisti rispetto a quelli elaborati in origine dall’European LeukemiaNet (ELN); - Per la MF, numero di risposte complete, risposte maggiori, risposte moderate e risposte minori definite in accordo ai criteri di risposta elaborati dall’European Myelofibrosis Network (EUMNET).
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint will be assessed at each quarterly visit and patients deriving clinical benefit from participating in the study will be allowed to continue study medication.
    L’endpoint primario sarà valutato ad ogni vista quadrimestrale; a tutti i pazienti che continuano ad avere un beneficio clinico dalla partecipazione allo studio, verrà consentito di proseguire il trattamento con il farmaco sperimentale.
    E.5.2Secondary end point(s)
    Exploratory endpoints: - The effect of Givinostat on each single response parameter according to the revised ELN (for PV and ET) and EUMNET response criteria (for MF); - Reduction of the JAK2V617F allele burden by quantitative RT-PCR; - Identification of potential other markers predictive of clinical benefit of Givinostat (e.g. potential PD markers).
    Endpoint esploratori: - Effetto di Givinostat su ciascun singolo parametro di risposta in accordo ai criteri di risposta rivisti rispetto a quelli elaborati in origine dall’ELN (per PV ed ET) e in accordo ai criteri di risposta EUMNET (per MF); - Riduzione del carico allelico JAK2V617F mediante l’analisi dell’RT-PCR quantitativa; - Identificazione di eventuali altri marcatori predittivi del beneficio clinico di Givinostat (come per esempio eventuali marcatori PD).
    E.5.2.1Timepoint(s) of evaluation of this end point
    The exploratory parameters will be evaluated by ad-hoc descriptive statistical analysis. Additional analyses could be performed to identify and quantify other molecular parameters of interest aimed at improving the understanding of cMPN and the activity of the drug.
    I parametri esploratori saranno valutati attraverso analisi statistiche descrittive ad-hoc. Potrebbero essere effettuate ulteriori analisi per identificare e quantificare altri parametri molecolari di interesse in modo da migliorare la conoscenza delle cMPN e dell’attività del farmaco.
    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 No
    E.8.1.1Randomised Information not present in EudraCT
    E.8.1.2Open Yes
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 concerned10
    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 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
    The end of the study (last patient last visit) will occur after all patients in the study have completed their last assessment as per protocol.
    La fine dello studio (ultima visita dell'ultimo paziente) avverrà dopo che tutti i pazienti nello studio avranno completato l'ultima valutazione prevista dal protocllo.
    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 months0
    E.8.9.1In the Member State concerned days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    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: 1
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1
    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 state1
    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)
    NA. This long-term study will recruit all patients who tolerated Givinostat and had clinical benefit at the end of core protocols in cMPN-Study DSC/07/2357/28,DSC/08/2357/38 and all further core protocols in cMPN-and/or all patients participating in compassionate use. Treatment will continue up to MA of Givinostat. However in case the approved label will not cover whole study population Givinostat will be given by Sponsor to those patients not fulfilling criteria for approved label.
    NA.Questo studio long-term arruolerà tutti i pazienti che hanno tollerato Givinostat e tratto beneficio clinico alla fine di protocolli base in CMPN-Studi DSC/07/2357/28,DSC/08/2357/38 e altri protocolli base in CMPN e/o tutti i paz che partecipano ad uso compass. La terapia continuerà fino all’AIC di Givinostat. Se la label approvata non coprirà tutta la popolazione in studio,Givinostat sarà dato dallo Sponsor a quei paz che non che non soddisfano criteri per la label approvata.
    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 Decision2013-01-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-12-14
    P. End of Trial
    P.End of Trial StatusOngoing
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