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    Summary
    EudraCT Number:2016-003552-75
    Sponsor's Protocol Code Number:CINC424A2411
    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:2020-12-15
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2016-003552-75
    A.3Full title of the trial
    A multicenter phase II, open label, single arm study to evaluate the efficacy and safety of ruxolitinib in the treatment of anemic myelofibrosis
    patients
    Studio multicentrico, di Fase II, in aperto, a braccio singolo, per valutare l’efficacia e la sicurezza d’impiego di ruxolitinib nel trattamento dei pazienti anemici con mielofibrosi
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and efficacy of ruxolitinib in anemic myelofibrosis patients
    Sicurezza ed afficacia d’impiego di ruxolitinib nel trattamento dei pazienti anemici con mielofibrosi
    A.3.2Name or abbreviated title of the trial where available
    REALISE
    REALISE
    A.4.1Sponsor's protocol code numberCINC424A2411
    A.5.4Other Identifiers
    Name:-Number:-
    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 SponsorNOVARTIS PHARMA SERVICES AG
    B.1.3.4CountrySwitzerland
    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 supportNovartis Pharma Services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNOVARTIS FARMA S.p.A
    B.5.2Functional name of contact pointDrug Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street AddressLargo Umberto Boccioni, 1
    B.5.3.2Town/ cityORIGGIO
    B.5.3.3Post code21040
    B.5.3.4CountryItaly
    B.5.4Telephone number0296541
    B.5.5Fax number029659066
    B.5.6E-mailinfo.studiclinici@novartis.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 nameruxolitinib
    D.3.2Product code [INC424]
    D.3.4Pharmaceutical form 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 INNRUXOLITINIB
    D.3.9.1CAS number 1092939-17-7
    D.3.9.2Current sponsor codeINC424
    D.3.9.3Other descriptive nameRUXOLITINIB PHOSPHATE
    D.3.9.4EV Substance CodeSUB32897
    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 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
    Treatment of anemic myelofibrosis patients
    Trattamento dei pazienti anemici con mielofibrosi
    E.1.1.1Medical condition in easily understood language
    Myelofibrosis patients with anemia
    Pazienti anemici con mielofibros
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10074691
    E.1.2Term Post polycythaemia vera myelofibrosis
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10074692
    E.1.2Term Post essential thrombocythaemia myelofibrosis
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the spleen length response rate at Week 24
    Determinare il tasso di risposta della lunghezza splenica alla settimana 24.
    E.2.2Secondary objectives of the trial
    - To determine the spleen length response rate at Week 48
    - To evaluate the effect of ruxolitinib on spleen length
    - To evaluate the effect of ruxolitinib on symptoms
    - To evaluate the effect of ruxolitinib on Patient Global Impression of Change (PGIC)
    - To evaluate the effect of ruxolitinib on transfusion requirements
    - Valutare la sicurezza d’impiego.
    - Determinare il tasso di risposta della lunghezza splenica alla settimana 48.
    - Valutare l’effetto di ruxolitinib sulla lunghezza splenica.
    - Valutare l’effetto di ruxolitinib sui sintomi.
    - Valutare l’effetto di ruxolitinib su Patient Global Impression of Change (PGIC)
    - Valutare l’effetto di ruxolitinib sulla necessità di trasfusioni.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Male or female patients aged = 18 years of age.
    - Patients must be diagnosed with PMF, according to the 2016 revised International Standard Criteria (Arber et al, 2016), PPV MF or PET-MF (Barosi 2008), irrespective of JAK2 mutation status.
    - Patients with palpable splenomegaly that is equal to or greater than 5cm below the left costal margin.
    - Patients with a hemoglobin less than 10 g/dL
    - Patients with a history of transfusions must have a documented transfusion record in the previous 12 weeks to baseline.
    - Patients with a peripheral blood blast percentage count of < 10%.

    Additional inclusion criteria as per full protocol may apply.
    1. Pazienti di entrambi i sessi, di età = 18 anni.
    2. I pazienti devono presentare una diagnosi di PMF, in base a “International Standard Criteria”, 2016, rivisti (Arber et al. 2016), PPV MF o PET-MF
    (Barosi 2008), indipendentemente dallo status della mutazione di JAK2.
    3. Pazienti con splenomegalia palpabile, uguale o superiore a 5 cm al di sotto del margine costale sinistro.
    4. Pazienti con emoglobina inferiore a 10 g/dL.
    5. I pazienti con un’anamnesi positiva per trasfusioni devono avere un registro documentato delle trasfusioni, nelle 12 settimane precedenti rispetto al basale.
    6. Pazienti con ECOG performance status di 0, 1 o 2.
    7. Pazienti con conta percentuale dei blasti nel sangue periferico < 10%.
    8. I pazienti devono aver presentato guarigione o stabilizzazione sufficiente di qualsiasi reazione avversa da farmaco associata ai trattamenti precedenti, prima dell’inizio del trattamento con ruxolitinib.
    E.4Principal exclusion criteria
    - Patients with prior treatment with any JAK1 or JAK2 inhibitor.
    - Patients with inadequate bone marrow reserve at baseline visit asdemonstrated by at least one of the following:
    - ANC that is = 1,000/µL.
    - Platelet count that is <50,000/µL without the assistance of growth factors, thrombopoietic factors or platelet transfusions.
    - Hemoglobin count that is = 6.5 g/dL despite transfusions.
    - Patients with severely impaired renal function
    - Patients with inadequate liver function
    - Patients being treated concurrently with a strong (potent) systemic inhibitor or inducer of CYP3A4 at the time of Screening
    - Acute viral hepatitis or active chronic hepatitis B or C infection.
    - History of progressive multifocal leuko-encephalopathy (PML)

    Additional exclusion criteria as per full protocol may apply.
    1. Pazienti con trattamento precedente con qualsiasi inibitore di JAK1 o JAK2.
    2. Pazienti con ipersensibilità nota a ruxolitinib o altri inibitori di JAK1/JAK2 o ai loro eccipienti.
    3. Pazienti eleggibili per il trapianto di cellule staminali ematopoietiche (il candidato idoneo e il donatore idoneo sono disponibili).
    4. Pazienti con riserva midollare inadeguata al basale, come dimostrato da almeno una delle condizioni seguenti:
    - ANC = 1.000/µL
    - Conta piastrinica < 50.000/µL senza il supplemento di fattori di crescita, fattori trombopoietici o trasfusioni piastriniche
    - Conta emoglobinica = 6,5 g/dL, nonostante le trasfusioni
    5. Pazienti con funzionalità renale gravemente compromessa, definita da: Clearance della creatinina inferiore a 30 mL/min.
    6. Pazienti con funzionalità epatica non adeguata come definito da una delle seguenti condizioni:
    - Bilirubina totale > 2,5 x ULN e successiva determinazione di bilirubina diretta > 2,5 x ULN
    - Alanina aminotrasferasi (ALT) > 2,5 x ULN
    - Aspartato aminotrasferasi (AST) > 2,5 x ULN
    7. Pazienti in trattamento concomitante con un forte (potente) inibitore o induttore sistemico del CYP3A4 al momento dello screening.
    8. Presenza di infezione batterica, micotica, parassitaria o virale in fase attiva che richiede terapia.
    9. Infezione del virus dell’immunodeficienza umana (HIV) nota o altra sindrome da immunodeficienza, quale agammaglobulinemia correlata al cromosoma X e immunodeficienza comune variabile.
    10. Epatite virale acuta o epatite cronica di tipo B o C attiva. I pazienti con infezione cronica non attiva (senza replicazione virale) potranno essere
    arruolati (vedi Sezione 7.2.2.7).
    11. Anamnesi positiva per leucoencefalopatia multifocale progressiva (PML).
    12. Pazienti con compromissione della funzionalità gastrointestinale (GI) o con patologie gastrointestinali che possono alterare significativamente l’assorbimento di ruxolitinib (ad es. colite ulcerosa, nausea non controllata,
    vomito, diarrea, sindrome da malassorbimento, resezione dell’intestino tenue).
    13. Anamnesi positiva o diagnosi attuale di cardiopatia clinicamente rilevante o non controllata, compresa qualsiasi condizione seguente:
    a. Infarto miocardico entro gli ultimi 6 mesi
    b. Insufficienza cardiaca congestizia non controllata
    c. Angina instabile entro gli ultimi 6 mesi
    d. Aritmia cardiaca clinicamente rilevante (sintomatica) (per esempio bradiaritmia, tachicardia ventricolare sostenuta e blocco AV di secondo o terzo grado clinicamente rilevante senza pacemaker).
    14. Qualsiasi condizione medica concomitante, non controllata che possa, secondo il giudizio dello sperimentatore, compromettere la sicurezza del paziente o l’aderenza al protocollo.
    15. Pazienti sottoposti a trattamento con un altro farmaco sperimentale o che sono stati trattati con un farmaco sperimentale entro 30 giorni o entro 5 emivite (qualunque sia più lungo), prima della somministrazione della prima dose del farmaco in studio.
    16. Pazienti con un’anamnesi positiva per neoplasia negli ultimi 3 anni, a eccezione di carcinoma a cellule squamose o a cellule basali trattato, in stadio precoce.
    17. Pazienti che non possono comprendere o non sono disposti a firmare un ICF.
    18. Gravidanza o allattamento
    19. Pazienti potenzialmente fertili, definite come donne che fisiologicamente possono iniziare una gravidanza, a meno che non utilizzino metodi
    contraccettivi di efficacia elevata, come definiti in seguito, per l’intera durata dello studio, compreso un periodo di 30 giorni di follow-up della sicurezza di impiego.
    Metodi contraccettivi di efficacia elevata comprendono:
    - Astinenza completa dai rapporti sessuali (se questa è coerente con lo stile di vita preferito e usuale della paziente). L’astinenza periodica
    (secondo calendario, ovulazione, sintotermica o post-ovulazione) e il coitus interruptus non sono metodi di contraccezione accettabili.
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of patients achieving a 50% reduction in spleen length at Week 24
    Percentuale di pazienti che hanno raggiunto una riduzione del 50% della lunghezza della milza alla
    settimana 24
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 24
    Settimana 24
    E.5.2Secondary end point(s)
    Proportion of patients achieving a 50% reduction in spleen length at week 48; Percent change from baseline in spleen length over time; Summary of the Modified MFSAF v2.0 and MF-7 over time; PGIC at each visit where measured; Summary of transfusions over time
    Percentuale di pazienti che hanno raggiunto una riduzione del 50% della lunghezza della milza alla settimana 48; Variazione percentuale dal basale della lunghezza della milza nel corso del tempo; Domande separate sulla inattività a calcolare il Modified MFSAF v2.0; Patient Global Impression of Change (PGIC); Domande separate sulle trasfusioni nel tempo
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 48; Week 48; Week 48; Week 48; Week 48
    Settimana 48; Settimana 48; Settimana 48; Settimana 48; Settimana 48
    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 Yes
    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 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 No
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Belgium
    Bulgaria
    Canada
    Chile
    Germany
    Greece
    Hungary
    Italy
    Japan
    Russian Federation
    Spain
    Turkey
    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 completion of the last follow up visit of the last patient on treatment with ruxolitinib.
    La fine dello studio (ultima visita dell'ultimo paziente) avverrà dopo il completamento dell'ultima visita di follow-up dell'ultimo paziente per il trattamento con ruxolitinib.
    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 months10
    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 months11
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 34
    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)
    Patients completing this trial may continue to be treated for their myelofibrosis with ruxolitinib or any other conventional therapy as judged by the physician and agreed by the patient. Should ruxolitinib be the therapy of choice, patients can continue treatment with commercial ruxolitinib according to local regulations. If ruxolitinib is
    not commercially available to patients after completing the study, Novartis will have a transition plan in place to ensure have access to
    ruxolitinib.
    I pazienti che hanno completato questo processo possono continuare ad essere trattati per la loro mielofibrosi con ruxolitinib o qualsiasi altra terapia convenzionale secondo il giudizio del medico e se accettato dal paziente. Qualora ruxolitinib fosse la terapia di elezione, i pazienti possono continuare il trattamento con ruxolitinib commerciale secondo le norme locali.
    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 Decision2017-01-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-04-27
    P. End of Trial
    P.End of Trial StatusCompleted
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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