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    Summary
    EudraCT Number:2020-000607-36
    Sponsor's Protocol Code Number:ACE-536-MF-002
    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: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 number2020-000607-36
    A.3Full title of the trial
    “A phase 3, double-blind, randomized study to compare the efficacy and safety of luspatercept (ACE-536) versus placebo in subjects with myeloproliferative neoplasm-associated myelofibrosis on concomitant JAK2 inhibitor therapy and who require red blood cell transfusions”
    “Studio di fase 3, in doppio cieco, randomizzato per confrontare l’efficacia e la sicurezza di luspatercept (ACE-536) rispetto al placebo in soggetti con mielofibrosi associata a neoplasia mieloproliferativa in terapia concomitante con un inibitore di JAK2 e che necessitano di trasfusioni di globuli rossi”
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate the benefit and safety of Luspatercept (ACE-536) in adults with myeloproliferative neoplasm-associated myelofibrosis on concomitant JAK2 inhibitor therapy and who require red blood cell transfusions
    Uno Studio per confrontare il beneficio e la sicurezza di Luspatercept (ACE-536) in aduti con neoplasia mieloproliferativa associata a mielofibrosi in terapia concomitante con un inibitore di JAK2 e che necessitano di trasfusioni di globuli rossi
    A.3.2Name or abbreviated title of the trial where available
    INDEPENDENCE
    INDEPENDENCE
    A.4.1Sponsor's protocol code numberACE-536-MF-002
    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 SponsorCELGENE CORPORATION
    B.1.3.4CountryUnited States
    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 supportCelgene Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCelgene Corporation
    B.5.2Functional name of contact pointClinicalTrialDisclosure
    B.5.3 Address:
    B.5.3.1Street Address86 Morris Avenue
    B.5.3.2Town/ citySummit, New Jersey
    B.5.3.3Post codeNJ 07901
    B.5.3.4CountryUnited States
    B.5.4Telephone number+19137096862
    B.5.6E-mailClinicalTrialDisclosure@celgene.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 Yes
    D.2.1.1.1Trade name Reblozyl
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/20/2255
    D.3 Description of the IMP
    D.3.1Product nameLuspatercept
    D.3.2Product code [ACE-536]
    D.3.4Pharmaceutical form Lyophilisate for 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 INNLuspatercept
    D.3.9.1CAS number 1373715-00-4
    D.3.9.2Current sponsor codeACE-536
    D.3.9.3Other descriptive nameLUSPATERCEPT
    D.3.9.4EV Substance CodeSUB179621
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number88
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    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) 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.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 Yes
    D.2.1.1.1Trade name Reblozyl
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/20/2255
    D.3 Description of the IMP
    D.3.1Product nameLuspatercept
    D.3.2Product code [ACE-536]
    D.3.4Pharmaceutical form Lyophilisate for 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 INNLuspatercept
    D.3.9.1CAS number 1373715-00-4
    D.3.9.2Current sponsor codeACE-536
    D.3.9.4EV Substance CodeSUB179621
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number38
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    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) 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 placeboSolution for injection/infusion
    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
    Anemia associated with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF)
    Anemia correlata a mielofibrosi (MF) associata a neoplasia mieloproliferativa (NMP).
    E.1.1.1Medical condition in easily understood language
    Anemia due to a bone marrow disorder resulting in abnormal production of blood cells
    Anemia causata da una malattia del midollo osseo che porta a una produzione anomala di cellule del sangue
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10077161
    E.1.2Term Primary myelofibrosis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10074689
    E.1.2Term Post polycythemia vera myelofibrosis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10074690
    E.1.2Term Post essential thrombocythemia myelofibrosis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10028537
    E.1.2Term Myelofibrosis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of luspatercept compared with placebo for the treatment of anemia in subjects with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) with concomitant JAK2 inhibitor therapy and who require red blood cell transfusions.
    Valutare l’efficacia di luspatercept rispetto a placebo per il trattamento dell’anemia nei soggetti con mielofibrosi (MF) associata a neoplasia mieloproliferativa (NMP) in terapia concomitante a base di inibitore di JAK2 e che necessitano di trasfusioni di globuli rossi.
    E.2.2Secondary objectives of the trial
    - To evaluate additional efficacy parameters of luspatercept compared with placebo;
    - To evaluate the the safety of luspatercept compared to placebo in subjects with MPN-associated MF as measured by the frequency and severity of adverse events (AEs), serious adverse events (SAEs), antidrug antibodies (ADA), and transformation to blast phase;
    - To evaluate pharmacokinetics (PK) for luspatercept in MPN-associated MF.
    - Valutare ulteriori parametri di efficacia di luspatercept rispetto a placebo;
    - Valutare la sicurezza di luspatercept rispetto a placebo in soggetti affetti da MF associata a NMP misurata in base a frequenza e gravità degli eventi avversi (adverse events, [AE]), eventi avversi seri (serious adverse events,[SAE]), anticorpi antifarmaco (antidrug antibodies,[ADA]), e trasformazione nella fase di blasti;
    - Valutare la farmacocinetica (pharmacokinetics, [PK]) per luspatercept nella MF associata a NMP.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject is =18 years of age at the time of signing the informed consent form (ICF).
    2. Subject has a diagnosis of primary myelofibrosis (PMF) according to the 2016 World Health Organization (WHO) criteria or diagnosis of postET or post-PV myelofibrosis according to the IWG-MRT 2007 criteria, confirmed by the most recent local pathology report.
    3. Subject is requiring RBC transfusions as defined as:
    a. Average RBC-transfusion frequency: 4 to 12 RBC units/12 weeks immediately up to randomization. There must be no interval > 6 weeks (42 days) without = 1 RBC transfusion.
    b. RBC transfusions are scored in determining eligibility when given for treatment
    of:
    - Symptomatic (ie, fatigue or shortness of breath) anemia with apretransfusion Hgb = 9.5 g/dL
    or
    - Asymptomatic anemia with a pretransfusion Hgb = 7g/dL
    c. RBC transfusions given for worsening of anemia due to bleeding or infections are not scored in determining eligibility.
    4. Subjects on continuous (eg, absent of dose interruptions lasting = 2 consecutive weeks) JAK2 inhibitor therapy as approved in the country of the study site for the treatment for MPN-associated MF as part of their standard-of-care therapy for at least 32 weeks, on stable daily dose for at least 16 weeks immediately up to the date of randomization and anticipated to be on a stable daily dose of that JAK2 inhibitor for at least 24 weeks after randomization.
    5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of =2.
    6. A female of childbearing potential (FCBP) for this study is defined as a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (eg, has had menses at any time in the preceding 24 consecutive months). FCBP participating in the study must:
    a. Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the study, and after end of IP. This applies even if the subject practices true abstinence* from heterosexual contact.
    b. Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, effective contraception** without interruption, 28 days prior to starting IP, during the study therapy (including dose interruptions), and for 12 weeks (approximately 5 times the mean terminal half-life of IP based on multiple-dose pharmacokinetics [PK] data) after discontinuation of study therapy.

    PLEASE REFER TO THE PROTOCOL FOR A COMPLETE LIST OF INCLUSION CRITERIA
    1. Il soggetto ha = 18 anni al momento della firma del modulo di consenso informato (Informed Consent Form, [ICF]).
    2. Soggetto con una diagnosi di mielofibrosi primaria (primary myelofibrosis, [PMF]) in conformità ai criteri dell’Organizzazione mondiale della Sanità (OMS) del 2016 o diagnosi di mielofibrosi post-trombocitemia essenziale (post-essential thrombocythemia, [post-ET]) o post-policitemia vera (post-polycythemia vera, [post-PV]), in base ai criteri IWG-MRT 2007 confermata dal più recente referto patologico locale.
    3. Il soggetto necessita di trasfusioni di RBC definite come:
    a. Frequenza media delle trasfusioni di RBC: da 4 a 12 unità di RBC/12 settimane immediatamente successive alla randomizzazione. Non deve esserci nessun intervallo > 6 settimane (42 giorni) senza = 1 trasfusione di RBC.
    b. Le trasfusioni di RBC vengono valutate per la determinazione dell’idoneità se sono somministrate per il trattamento di:
    - Anemia sintomatica (ossia affaticamento o respiro affannoso) con una Hgb pretrasfusione = 9,5 g/dL o
    - Anemia asintomatica con una Hgb pretrasfusione pari a = 7 g/dL
    c. Le trasfusioni di RBC somministrate per il peggioramento dell’anemia dovuta a sanguinamento o infezioni non vengono valutate nel determinare l’idoneità.
    4. I soggetti in terapia continua (ad es. priva di interruzioni della dose di durata =2 settimane consecutive) con inibitore di JAK2 come approvata nel paese del centro dello studio per il trattamento di MF associata a NMP nell’ambito della terapia standard di cura per almeno 32 settimane, durante il trattamento con dose giornaliera stabile per almeno 16 settimane immediatamente fino alla data della randomizzazione e con previsione di trattamento con dose giornaliera stabile di tale inibitore di JAK2 per almeno 24 settimane dopo la randomizzazione.
    5. Il soggetto presenta un punteggio dello stato di validità secondo l’Eastern Cooperative Oncology Group (ECOG) (Gruppo cooperativo orientale di oncologia) =2.
    6. Un soggetto di sesso femminile in età fertile (female of childbearing potential [FCBP]) per il presente studio si definisce come una donna che: 1) ha raggiunto il menarca in un dato momento, 2) non è stata sottoposta a isterectomia o a ooforectomia bilaterale oppure 3) non si trova in stato di post-menopausa naturale (l’amenorrea dovuta a terapia per il tumore non esclude la potenziale fertilità) da almeno 24 mesi consecutivi (ovvero ha avuto cicli mestruali in un momento qualsiasi dei precedenti 24 mesi consecutivi). Le FCBP che partecipano allo studio devono:
    a. Sottoporsi a 2 test di gravidanza con esito negativo verificato dallo sperimentatore prima di iniziare la terapia dello studio. La donna deve acconsentire a sottoporsi a test di gravidanza continui durante lo studio e dopo la fine del trattamento con IP, applicabile anche nel caso in cui il soggetto pratichi l’astinenza completa* dal contatto eterosessuale.
    b. Impegnarsi all'astinenza completa* dal contatto eterosessuale (che deve essere riesaminata con cadenza mensile e documentata) o accettare di usare ed essere in grado di attenersi a un metodo di contraccezione efficace** senza interruzione, 28 giorni prima di iniziare il trattamento con il prodotto sperimentale, durante la terapia in studio (incluse le interruzioni della dose) e per 12 settimane (circa 5 volte l'emivita terminale media del farmaco sperimentale sulla base di dati di farmacocinetica, [PK] per dosi multiple) dopo l'interruzione della terapia in studio.

    PER UNA LISTA COMPLETA DEI CRITERI DI INCLUSIONE FARE RIFERIMENTO AL PROTOCOLLO
    E.4Principal exclusion criteria
    1. Subject with anemia from cause other than MPN-associated MF or JAK2 inhibitor therapy (eg, iron deficiency, vitamin B12 and/or folate deficiencies, autoimmune or hemolytic anemia, infection, or any type of known clinically significant bleeding or sequestration).
    2. Subject use of hydroxyurea, immunomodulatory compounds such as pomalidomide, thalidomide, ESAs, androgenic steroids or other drugs with potential effects on hematopoiesis = 8 weeks immediately up to the date of randomization.
    a. Systemic corticosteroids are permitted for nonhematological conditions providing the subject is receiving a constant dose equivalent to = 10 mg prednisone for the 4 weeks immediately up to randomization.
    b. Iron chelation therapy (ICT) is permitted providing the subject is receiving a stable dose for the 8 weeks immediately up to randomization.
    3. Subject with any of the following laboratory abnormalities at screening:
    a. Neutrophils: < 1 x 10^9/L
    b. White blood count (WBC): > 100 x 10^9/L
    c. Platelets: the lowest allowable level as approved for the concomitant JAK2 inhibitor but not < 25 x 10^9/L or > 1000 x 10^9/L
    d. Peripheral blood myeloblasts: > 5%
    e. Estimated glomerular filtration rate: < 40 mL/min/1.73 m2 (via the 4variable modification of diet in renal disease [MDRD] formula) or nephrotic subjects (eg, urine albumin-to-creatinine ratio > 3500 mg/g)
    f. Aspartate aminotransferase (AST) or alanine aminotransferase: (ALT) > 3.0 x upper limit of normal (ULN)
    g. Direct bilirubin: = 2 x ULN
    - Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (eg, ineffective erythropoiesis)
    4. Subject with uncontrolled hypertension, defined as repeated elevations of systolic blood pressure = 140 mmHg or diastolic blood pressure = 90 mmHg, that is not resolved at the time of randomization.
    5. Subject with prior history of malignancies, other than disease under study, unless the subject has been free of the disease for = 3 years. However, subject with the following history/concurrent conditions is allowed:
    a. Basal or squamous cell carcinoma of the skin
    b. Carcinoma in situ of the cervix
    c. Carcinoma in situ of the breast
    d. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)
    6. Subject with prior hematopoietic cell transplant or subject anticipated to receive a hematopoietic cell transplant during the 24 weeks from the date of randomization.
    7. Subject with stroke, myocardial infarction, deep venous thrombosis, pulmonary or arterial embolism within 6 months immediately up to the date of randomization.
    8. Subject with major surgery within 2 months up to the date of randomization. Subject must have completely recovered from any previous surgery immediately up to the date of randomization.
    9. Subject with a major bleeding event (defined as symptomatic bleedingin a critical area or organ and/or bleeding causing a decrease in Hgb of = 2 g/dL or leading to transfusion of = 2 units of packed red cells) in the last 6 months prior to the date of randomization.

    PLEASE REFER TO THE PROTOCOL FOR A COMPLETE LIST OF EXCLUSION CRITERIA
    1. Soggetto con anemia da cause diverse da MF associata a NMP o terapia con inibitore di JAK2 (ad es., carenza di ferro, vitamina B12 e/o carenze di folato, anemia autoimmune o emolitica, infezione, o qualsiasi tipo di sanguinamento o sequestro noto clinicamente significativo).
    2. Uso da parte del soggetto di idrossiurea, composti immunomodulatori come pomalidomide, talidomide, ESA, steroidi androgenici o altri farmaci con potenziali effetti sull’ematopoiesi = 8 settimane immediatamente precedenti alla data di randomizzazione.
    a. I corticosteroidi sistemici sono consentiti per le malattie non ematologiche purché il soggetto stia ricevendo una dose costante equivalente a = 10 mg di prednisone per le 4 settimane immediatamente precedenti la randomizzazione.
    b. La terapia ferrochelante (iron chelation therapy [ICT]) è consentita purché il soggetto stesse ricevendo una dose stabile nelle 8 settimane precedenti la randomizzazione.
    3. Il soggetto presenta una qualsiasi delle seguenti anomalie di laboratorio allo screening:
    a. neutrofili: <1 x 10^9/L
    b. conta dei globuli bianchi (WBC): > 100 x 10^9/L
    c. piastrine: livello minimo consentito come approvato per inibitore di JAK2 concomitante ma non < 25 x 10^9/L o > 1000 x 10^9/L
    d. mieloblasti di sangue periferico:> 5%
    e. velocità di filtrazione glomerulare stimata: < 40 ml/min/1,73 m2 (tramite la formula a 4 variabili di modifica della dieta nella malattia renale (Modification of Diet in Renal Disease [MDRD]) o soggetti nefrotici (ad es., rapporto albumina nelle urine/creatinina >3500 mg/g)
    f. aspartato aminotransferasi (AST) o alanina aminotransferasi: (ALT) > 3,0 x limite superiore della norma (upper limit of normal, [ULN])
    g. bilirubina diretta: = 2 x ULN
    - Livelli superiori sono accettabili se possono essere attribuiti a distruzione attiva del precursore dei globuli rossi nel midollo osseo (ad es., eritropoiesi inefficace)
    4. Soggetti con ipertensione non controllata, definita come incrementi ripetuti di pressione arteriosa sistolica =140 mmHg o pressione arteriosa diastolica =90 mmHg, non risolti al momento della randomizzazione.
    5. Soggetto con anamnesi pregressa di tumori maligni diversi dalla malattia oggetto di studio, a meno che il soggetto non presenti tracce di malattia da =3 anni. Sono tuttavia ammessi i soggetti con le seguenti anamnesi/condizioni concomitanti:
    a. carcinoma della pelle a cellule basali o cellule squamose
    b. carcinoma della cervice uterina in situ
    c. carcinoma mammario in situ
    d. riscontro istologico accidentale di carcinoma prostatico (T1a o T1b usando il sistema di classificazione clinica di tumore, nodi, metastasi [TNM])
    6. Soggetto con precedente trapianto di cellule ematopoietiche o trapianto di cellule ematopoietiche programmato per il soggetto durante le 24 settimane dalla data della randomizzazione.
    7. Soggetto con ictus, infarto miocardico, trombosi venosa profonda, embolia polmonare o arteriosa entro i 6 mesi immediatamente precedenti la data di randomizzazione.
    8. Soggetto sottoposto a intervento di chirurgia maggiore entro 2 mesi prima della data di randomizzazione. Il soggetto deve essersi completamente ristabilito da qualsiasi precedente intervento chirurgico nel periodo immediatamente precedente la data di randomizzazione.
    9. Soggetto che presenta evento di sanguinamento maggiore (definito da sanguinamento sintomatico in un'area o un organo critico e/o sanguinamento che causa una diminuzione nell’emoglobina di = 2 g/dl o che richiede trasfusione di = 2 unità di globuli rossi) negli ultimi 6 mesi prima della data di randomizzazione.

    PER UNA LISTA COMPLETA DEI CRITERI DI ESCLUSIONE FARE RIFERIMENTO AL PROTOCOLLO
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of subjects who become RBC transfusion free during any consecutive 12-week period
    Percentuali di soggetti che diventano liberi da trasfusioni di globuli rossi durante qualsiasi periodo di 12 settimane consecutive
    E.5.1.1Timepoint(s) of evaluation of this end point
    Any consecutive "rolling" 12-week period starting from randomization up to and including Week 24
    Qualsiasi periodo “continuo” di 12-settimane consecutive a partire dalla randomizzazione fino alla Settimana 24 compresa
    E.5.2Secondary end point(s)
    1) Proportion of subjects who become RBC-transfusion free over any consecutive 16-week period
    2) Maximum duration of RBC-TI response
    3) Proportion of subjects who reduce their transfusion burden by = 50% and by = 4 units from baseline over any consecutive 12-week period
    4) Maximum duration of when subjects reduce their transfusion burden by = 50% and by = 4 units from baseline over any consecutive 12-week period
    5)Proportion of subjects who become RBC-transfusion free over any consecutive 12-week period
    6) Proportion of subjects who become RBC-transfusion free over any consecutive 16-week period
    7) Mean change in transfusion burden (RBC units) from baseline
    8) Cumulative response duration for subjects achieving multiple episodes of RBC-TI 12
    9) Proportion of subjects achieving a mean Hgb increase = 1 g/dL from baseline over any consecutive 12-week period in absence of RBC transfusions
    10) Change in serum ferritin from baseline.
    1) Percentuale di soggetti che diventano liberi da trasfusioni di globuli rossi durante qualsiasi periodo di 16 settimane consecutive
    2) Durata massima della risposta RBC-TI
    3) Percentuale di soggetti che riducono il loro carico trasfusionale di = 50% e di = 4 unità dal basale nell’arco di qualsiasi periodo di 12-settimane consecutive
    4) Durata massima del periodo in cui i soggetti riducono il loro carico trasfusionale di = 50% e di = 4 unità rispetto al basale nell’arco di qualsiasi periodo di 12-settimane consecutive
    5) Percentuale di soggetti che diventano liberi da trasfusioni di globuli rossi nell’arco di qualsiasi periodo di 12 settimane consecutive
    6) Percentuale di soggetti che diventano liberi da trasfusioni di globuli rossi nell’arco di qualsiasi periodo di 16 settimane consecutive
    7) Variazione media del carico di trasfusioni (unità di globuli rossi) rispetto al basale
    8) Durata cumulativa di risposta per soggetti che ottengono episodi molteplici di RBC-TI 12
    9) Percentuale di soggetti che ottengono un incremento medio di Hgb = 1 g/dL rispetto al basale nell’arco di qualsiasi periodo di 12-settimane consecutive in assenza di trasfusioni di globuli rossi
    10) Variazione dei livelli di ferritina sierica rispetto al basale.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1)Any consecutive "rolling" 16-week period starting from randomization up to and including Week 24
    2)Randomization up to end of treatment
    3)Randomization up to and including Week 24
    4)Randomization up to end of treatment
    5)Any consecutive "rolling" 12-week period from randomization up to end of treatment
    6)Any consecutive "rolling" 16-week period from randomization up to end of treatment
    7)Randomization up to and including Week 24
    8)Randomization up to end of treatment
    9)Any consecutive "rolling" 12-week period starting from randomization up to and including Week 24; Randomization up to end of treatment
    10)Randomization up to and including Week 24; Randomization up to
    end of treatment
    1) Qualsiasi periodo “continuo” di 16 settimane consecutive a partire dalla randomiz. fino alla Settimana 24 compresa
    2) Dalla randomiz. fino a fine tratt
    3) Dalla randomiz. fino alla Settimana 24 compresa
    4) Dalla randomiz. fino a fine tratt
    5) Qualsiasi periodo “continuo” di 12 settimane consecutive a partire dalla randomiz fino a fine tratt
    6) Qualsiasi periodo “continuo” di 16 settimane consecutive a partire dalla randomiz fino a fine tratt
    7) Dalla randomiz. fino alla Settimana 24 compresa
    8) Dalla randomiz. fino a fine tratt
    9) Qualsiasi periodo “continuo” di 12 settimane consecutive a partire dalla randomizzazione fino alla Settimana 24 compresa; dalla randomizzazione fino a fine tratt
    10) Dalla randomizzazione fino alla Settimana 24 compresa; dalla randomizzazione fino a fine tratt
    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 Yes
    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
    Biomarkers
    Biomarcatori
    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) Yes
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA99
    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
    Australia
    Austria
    Belgium
    Canada
    Czechia
    France
    Germany
    Greece
    Hong Kong
    Ireland
    Israel
    Italy
    Japan
    Korea, Republic of
    Netherlands
    Poland
    Russian Federation
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    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 Trial is defined as either the date of the last visit of the last subject to complete the post-treatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date.
    La conclusione della sperimentazione è definita come la data dell'ultima visita dell'ultimo soggetto che conclude il follow-up post-trattamento o la data di ricezione dell'ultimo dato dall'ultimo soggetto, elemento necessario per un'analisi primaria, secondaria e/o esplorativa, come preliminarmente specificato nel protocollo, a seconda di quale delle due date sia posteriore.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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: 62
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 247
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 204
    F.4.2.2In the whole clinical trial 309
    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)
    Subjects who discontinue the study treatment may continue on available standard of care per physician discretion. As subjects are randomized 2:1 in this study, neither subjects nor sites know the treatment received until the study has been unblinded.
    I soggetti che interrompono il trattamento in studio possono continuare con il trattamento standard di cura disponibile a discrezione del medico. Poiché i soggetti sono randomizzati a un rapporto di 2:1 in questo studio, né i soggetti né i centri sono a conoscenza del trattamento ricevuto fino all’apertura del cieco dello studio.
    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 Decision2021-01-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-02-16
    P. End of Trial
    P.End of Trial StatusOngoing
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