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    Summary
    EudraCT Number:2015-003454-41
    Sponsor's Protocol Code Number:ACE-536-MDS-001
    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:2021-01-15
    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 number2015-003454-41
    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 For The Treatment Of Anemia Due To IPSS-R Very Low, Low, Or Intermediate Risk Myelodysplastic Syndromes In Subjects With Ring Syderoblasts. Who Require Red Blood Cell Transfusion
    Studio di fase 3, in doppio cieco, randomizzato per confrontare l'efficacia e la sicurezza di Luspatercept (ACE-536) verso placebo nel trattamento dell'anemia dovuta a sindrome mielodisplastica a rischio IPSS-R molto basso, basso o intermedio in soggetti con sideroblasti ad anello che necessitano di trasfusioni di globuli rossi.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study To Compare The Benefit And Safety Of Luspatercept (ACE-536) Versus Placebo in subjects with lack of normal Red Blood Cells Requiring Transfusion due to myelodysplastic syndromes (MDS) with ring sideroblasts
    Studio per confrontare i benefici e la sicurezza di Luspatercept (ACE-536) rispetto al placebo in soggetti con mancanza di normali globuli rossi che necessitano di trasfusioni a causa di sindromi mielodisplastiche (MDS) con sideroblasti ad anello
    A.3.2Name or abbreviated title of the trial where available
    MEDALIST
    MEDALIST
    A.4.1Sponsor's protocol code numberACE-536-MDS-001
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN00000000
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00000000
    A.5.3WHO Universal Trial Reference Number (UTRN)U0000-0000-0000
    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 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 organisationPPD
    B.5.2Functional name of contact pointPPD Project Manager
    B.5.3 Address:
    B.5.3.1Street AddressC/Titán, 15 6th floor
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28045
    B.5.3.4CountrySpain
    B.5.4Telephone number00349177427000
    B.5.5Fax number0034917742701
    B.5.6E-mailMarta.Sanchez-Migallon@ppdi.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.2.1.1.1Trade name --
    D.2.1.1.2Name of the Marketing Authorisation holder---
    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/3/14/1331
    D.3 Description of the IMP
    D.3.1Product nameLuspatercept
    D.3.2Product code [ACE-536]
    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 INNLuspatercept
    D.3.9.1CAS number 1373715-00-4
    D.3.9.2Current sponsor codeACE-536
    D.3.9.3Other descriptive nameLuspatercept
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number375
    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 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.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1331
    D.3 Description of the IMP
    D.3.1Product nameLuspatercept
    D.3.2Product code [ACE-536]
    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 INNLuspatercept
    D.3.9.1CAS number 1373715-00-4
    D.3.9.2Current sponsor codeACE-536
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number875
    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 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
    Subjects with ring sideroblasts who require regular Red Blood Cell (RBC) Transfusions due to anemia due to Myelodysplastic Syndromes (MDS)
    Soggetti con sideroblasti ad anello che necessitano di regolari trasfusioni di globuli rossi (RBC) a causa di anemia dovuta a sindromi mielodisplastiche (MDS)
    E.1.1.1Medical condition in easily understood language
    Subjects who require regular Red Blood Cell (RBC) Transfusions due to red blood cell count being lower than normal lead by a blood disorder due to damage in the blood-forming cells in the bone marrow
    Sogg che necessitano di reg trasfusioni di globuli rossi (RBC) a causa di conte dei globuli rossi inferiori alla norma provocate da un disturbo ematico dovuto a un danno alle cellule preposte alla for
    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 LLT
    E.1.2Classification code 10002272
    E.1.2Term Anemia
    E.1.2System Organ Class 100000004851
    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 RBC transfusion independence (RBC-TI) of luspatercept compared with placebo for the treatment of anemia due to IPSS-R very low, low, or intermediate risk MDS in subjects with ring sideroblasts (= 15%) who require RBC transfusions
    Valutare l'indipendenza da trasfusioni di RBC (RBC-TI) di luspatercept rispetto al placebo per il trattamento dell'anemia dovuta a MDS a rischio molto basso, basso o intermedio secondo IPSS-R in soggetti con sideroblasti ad anello (= 15%) che necessitano di trasfusioni di RBC
    E.2.2Secondary objectives of the trial
    1. To assess the safety and tolerability of luspatercept compared with placebo
    2. To evaluate the effect of luspatercept on reduction in RBC transfusions, increase in hemoglobin, duration of RBC-TI, improvement
    in health-related quality of life (HRQoL) (ie, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ-C30]), increase in neutrophils, increase in platelets, decrease in serum ferritin, decrease in iron chelation therapy use, and time to RBCTI compared with placebo
    3. To evaluate population pharmacokinetics and exposure-response relationships for luspatercept in MDS subjects
    1 Valutare la sicurezza e la tollerabilit¿ di luspatercept rispetto al placebo
    2 Valutare l'effetto di luspatercept sulla riduzione di trasfusioni di RBC, l'aumento dell'emoglobina, la durata della RBC-TI, il miglioramento della qualit¿ di vita correlata alla salute (HRQoL) (questionario sulla qualit¿ di vita redatto dall'Organizzazione europea per la ricerca e il trattamento del cancro [EORTC QLQ-C30]), l'aumento dei neutrofili, l'aumento delle piastrine, la diminuzione della ferritina nel siero, la diminuzione dell'uso di terapie ferrochelanti e il tempo alla RBC-TI rispetto al placebo
    3 Valutare la farmacocinetica della popolazione e le correlazioni esposizione-risposta per luspatercept in soggetti con MDS
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject is = 18 years of age the time of signing the informed consent form (ICF).
    2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
    3. Documented diagnosis of MDS according to WHO 2008 classification (Appendix B) that meets IPSS-R classification (Greenberg, 2012; Appendix D) of very low, low, or intermediate risk disease, and: Ring sideroblast = 15% of erythroid precursors in bone marrow, and < 5% blasts in bone marrow
    4. Refractory or intolerant to, or ineligible for, prior ESA treatment, as defined by any one of the following:
    - Refractory to prior ESA treatment - documentation of non-response or response that is no longer maintained to prior ESA-containing regimen,
    either as single agent or combination (eg, with G-CSF); ESA regimen must have been either:
    a) recombinant human erythropoietin (rHu EPO) = 40,000 IU/wk for at least 8 doses or equivalent;
    OR
    b) darbepoetin alpha = 500 µg Q3W for at least 4 doses or equivalent;
    - Intolerant to prior ESA treatment - documentation of discontinuation of prior ESAcontaining regimen, either as single agent or combination (eg, with G-CSF), at any time after introduction due to intolerance or an adverse event
    - ESA ineligible - Low chance of response to ESA based on endogenous serum erythropoietin level > 200 U/L for subjects not previously treated with ESAs
    5. If previously treated with ESAs, granulocyte colony-stimulating factor
    (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF),
    must have been discontinued = 6 weeks prior to date of randomization.
    6. Requires RBC transfusions, as documented by the following criteria:
    - average transfusion requirement of = 2 units/8 weeks of pRBCs confirmed for a minimum of 16 weeks immediately preceding randomization.
    - no consecutive 56-day period that was RBC transfusion-free during the 16 weeks immediately preceding randomization
    7. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2
    8. Females of childbearing potential (FCBP) must:
    a) Have two negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. 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 prior to each IP administration or on a monthly basis [eg, in the event of dose delays] and source documented) or agree to use, and be able to comply with, effective contraception without interruption, 5 weeks prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks after discontinuation of study therapy.
    9. Male subjects must practice true abstinence* (which must be reviewed prior to each IP administration or on a monthly basis [eg, in the event of dose delays]) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 12 weeks following investigational product discontinuation, even if he has undergone a successful vasectomy.
    10. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
    1.Il soggetto deve avere = 18 anni al momento della firma del modulo di consenso informato (ICF).
    2.Il soggetto deve comprendere e firmare volontariamente un ICF prima che sia effettuata qualsiasi valutazione/procedura correlata allo studio.
    3.Diagnosi documentata di MDS secondo la classificazione del 2008 dell'OMS (Appendice B) che soddisfi la classificazione IPSS-R (Greenberg, 2012; Appendice D) di malattia a rischio molto basso, basso o intermedio, e: Sideroblasti ad anello = 15% di precursori eritroidi nel midollo osseo, e < 5% di blasti nel midollo osseo
    4.Soggetto refrattario o intollerante a, o ineleggibile per, precedente trattamento con ESA, come definito da uno dei seguenti elementi:
    - Refrattarietà a precedente trattamento con ESA: documentazione di mancata risposta o risposta che non è più mantenuta con il precedente regime contenente ESA, come agente singolo o in combinazione (ad es., con G-CSF); il regime a base di ESA deve essere stato uno dei seguenti:
    a) eritropoietina umana ricombinante (rHu-EPO) = 40.000 IU/sett. per almeno 8 dosi o equivalente;
    OPPURE
    b) darbepoetina alfa = 500 µg Q3W per almeno 4 dosi o equivalente;
    - Intolleranza a precedente trattamento con ESA: documentazione di interruzione di precedente regime contenente ESA, come agente singolo o in combinazione (ad es., con G-CSF), in qualsiasi momento dopo l'introduzione a causa di intolleranza o di un evento avverso
    - Ineleggibilità al trattamento con ESA: scarsa probabilità di risposta all'ESA in base a livelli di eritropoietina endogena nel siero > 200 U/L per soggetti precedentemente non trattati con ESA
    5.Precedenti trattamenti con ESA o con il fattore di stimolazione delle colonie di granulociti (G-CSF),o con il fattore di stimolazione delle colonie di granulociti macrofagi (GM-CSF), entrambi i fattori devono essere stati interrotti = 6 settimane prima della data di randomizzazione.
    6.Il soggetto necessita di trasfusioni di RBC, come documentato dai seguenti criteri:
    - necessità media di trasfusioni = 2 unità/8 settimane di pRBC confermata per un minimo di 16 settimane subito prima della randomizzazione.
    - periodo di 56 giorni non consecutivi senza trasfusioni di RBC nelle 16 settimane immediatamente precedenti la randomizzazione
    7.Punteggio ECOG (Eastern Cooperative Oncology Group) pari a 0, 1 o 2.
    8.Le donne in età fertile (FCBP - female of child bearing potential) devono:
    a)Presentare due test di gravidanza negativi verificati dallo Sperimentatore prima di iniziare la terapia dello studio. Accettare di sottoporsi a test di gravidanza per tutta la durata dello studio e dopo la conclusione del trattamento dello studio. Questo si applica anche se il soggetto pratica astinenza totale dai rapporti eterosessuali.
    b)Se sessualmente attivi, impegnarsi all'astinenza totale dai rapporti eterosessuali (che deve essere riesaminata prima di ogni somministrazione del farmaco sperimentale (IP) o a cadenza mensile [ad es., nel caso di ritardi della somministrazione] e opportunamente documentate) o accettare di usare ed essere in grado di attenersi a un metodo di contraccezione efficace senza interruzione, 5 settimane prima dell'inizio del trattamento con il farmaco sperimentale, durante il periodo di terapia (incluse le interruzioni della somministrazione) e per 12 settimane dopo l'interruzione della terapia in studio.
    9.I soggetti di sesso maschile devono praticare l'astinenza totale* (che deve essere riesaminata prima di ogni somministrazione di IP o a cadenza mensile [ad es., nel caso di ritardi della somministrazione]) o accettare di utilizzare il preservativo durante i rapporti sessuali con una donna in gravidanza o con una donna in età fertile nel corso della partecipazione allo studio, durante le interruzioni della somministrazione e per almeno 12 settimane dopo l'interruzione del trattamento con farmaco sperimentale, anche in caso di intervento efficace di vasectomia.
    E.4Principal exclusion criteria
    1. Prior therapy with disease modifying agents or experimental agents for underlying MDS disease
    2. Previously treated with either luspatercept (ACE-536) or sotatercept (ACE-011)
    3. MDS associated with del 5q cytogenetic abnormality
    4. Secondary MDS, ie, MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases.
    5. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or
    gastrointestinal bleeding
    6. Prior allogeneic or autologous stem cell transplant
    7. Known history of diagnosis of AML
    8. Use of any of the following within 5 weeks prior to randomization:
    - Anticancer cytotoxic chemotherapeutic agent or treatment
    - Corticosteroid, except for subjects on a stable or decreasing dose for = 1 week prior to randomization for medical conditions other than MDS
    - Iron-chelating agents, except for subjects on a stable or decreasing dose for at least 8 weeks prior to randomization
    - Other RBC hematopoietic growth factors (eg, Interleukin-3)
    9. Uncontrolled hypertension, defined as repeated elevations of diastolic blood pressure (DBP) = 100 mmHg despite adequate treatment.
    10. Absolute neutrophil count (ANC) < 500/µL (0.5 x 109/L)
    11. Platelet count < 50,000/µL (50 x 109/L)
    12. Estimated glomerular filtration rate (eGRF) or creatinine clearance < 40 mL/min
    13. Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) or alanine aminotransferase/serum glutamic
    pyruvic transaminase (ALT/SGPT) = 3.0 x upper limit of normal (ULN)
    14. Total bilirubin = 2.0 x ULN.
    - Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective
    erythropoiesis).
    - Subjects are excluded if there is evidence of autoimmune hemolytic anemia manifested as a corrected reticulocyte count of > 2% with either
    a positive Coombs' test or over 50% indirect bilirubin
    15. Prior history of malignancies, other than MDS, unless the subject has been free of the disease for = 5 years. However, subjects with the following history/concurrent conditions are allowed:
    - Basal or squamous cell carcinoma of the skin
    - Carcinoma in situ of the cervix
    -Carcinoma in situ of the breast
    - Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)
    16. Major surgery within 8 weeks prior to randomization. Subjects must have completely recovered from any previous surgery prior to
    randomization
    17. History of stroke, deep venous thrombosis (DVT), pulmonary or arterial embolism within 6 months prior to randomization
    18. Pregnant or breastfeeding females
    19. Myocardial infarction, uncontrolled angina, uncontrolled heart failure, or uncontrolled cardiac arrhythmia as determined by the investigator within 6 months prior to randomization
    20. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment), known Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV) infection, and/or Hepatitis C (HCV) infection.
    21. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product.
    22. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
    23. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
    24. Subject has any condition or concomitant medication that confounds the ability to interpret data from the study.
    1. Precedente terapia con agenti modificanti la malattia o agenti sperimentali relativi alla patologia MDS in studio.
    2. Precedente trattamento con luspatercept (ACE-536) o sotatercept (ACE-011)
    3. MDS associata con anomalia citogenetica del 5q
    4. MDS secondaria, ovvero MDS notoriamente causata da lesione chimica o trattamento con chemioterapia e/o radiazioni per altre malattie
    5. Anemia nota clinicamente significativa dovuta a mancanza di ferro, vitamina B12 o folato oppure anemia emolitica autoimmune o ereditaria oppure sanguinamento gastrointestinale.
    6. Precedente trapianto di cellule staminali autologo o allogeno
    7. Anamnesi nota di diagnosi di AML
    8. Uso di uno qualsiasi dei seguenti farmaci nelle 5 settimane precedenti la randomizzazione:
    - Trattamento o agente chemioterapico citotossico anticancro
    - Corticosteroidi, eccetto per soggetti in terapia con una dose stabile o decrescente per = 1 settimana prima della randomizzazione per condizioni mediche diverse da MDS
    - Agenti ferrochelanti, eccetto per soggetti in terapia con una dose stabile o decrescente per almeno 8 settimane prima della randomizzazione
    - Altri fattori di crescita ematopoietica RBC (ad es., interleuchina-3)
    9. Ipertensione non controllata, definita come aumenti ripetuti della pressione arteriosa diastolica (DBP) = 100 mmHg nonostante adeguato trattamento.
    10. Conta assoluta dei neutrofili (ANC) < 500/µL (0,5 x 109/L)
    11. Conta piastrinica < 50.000/µL (50 x 109/L);
    12. Velocità di filtrazione glomerulare stimata (eGRF) o clearance della creatinina < 40 ml/min
    13. Aspartato aminotransferasi sierica/transaminasi sierica glutammico-ossalacetica (ALT/SGOT) o alanina aminotransferasi/transaminasi sierica glutammico-piruvica (ALT/SGPT) = 3,0 volte il limite superiore della norma (ULN)
    14. Bilirubina totale >2,0 x ULN (limite normale superiore)
    Livelli più elevati sono accettabili se attribuibili a un’attiva distruzione di precursori dei globuli rossi all'interno del midollo osseo (ad es. eritropoiesi inefficiente).
    I soggetti sono esclusi in caso di evidenza di anemia emolitica autoimmune che si manifesta come conta corretta dei reticolociti > 2% con test di Coombs positivo o bilirubina indiretta superiore al 50%
    15. Storia precedente di tumori maligni diversi da MDS, a meno che il soggetto non presenti tracce di malattia da > 5 anni. Sono tuttavia ammessi i soggetti con storia/l condizioni concomitanti seguenti:
    - Carcinoma della pelle a cellule basali o cellule squamose
    - Carcinoma in situ della cervice
    - Carcinoma mammario in situ
    - Riscontro istologico accidentale di cancro alla prostata (T1a o T1b usando il sistema di classificazione clinica di tumore, nodi, metastasi [TNM])
    16. Intervento chirurgico significativo nelle 8 settimane precedenti la randomizzazione. I soggetti devono essersi completamente ristabiliti da eventuali precedenti interventi chirurgici prima della randomizzazione
    17. Anamnesi di ictus, trombosi venosa profonda (DVT), embolia polmonare o arteriosa nei 6 mesi precedenti la randomizzazione
    18. Donne in gravidanza o in allattamento
    19. Infarto del miocardio, angina non controllata, insufficienza cardiaca non controllata o aritmia cardiaca non controllata come stabilito dallo sperimentatore nei 6 mesi precedenti la randomizzazione
    20. Infezione batterica, fungina o virale sistemica non controllata (definita come segni/sintomi in atto correlati all'infezione senza miglioramento nonostante adeguata terapia antibiotica, antivirale e/o altro trattamento), nota infezione da virus dell'immunodeficienza umana (HIV), infezione attiva da virus dell'epatite B (HBV) e/o infezione da epatite C (HCV). Analisi locali che confermino una condizione di HIV, Epatite B ed Epatite C non devono essere state eseguite prima di 4 settimane dalla data della firma dell'ICF.
    21. Anamnesi di grave reazione allergica o anafilattica o ipersensibilità alle proteine ricombinanti o agli eccipienti del farmaco sperimentale.
    E.5 End points
    E.5.1Primary end point(s)
    Red Blood Cell Transfusion Independence (RBC-TI) = 8 weeks - Proportion of subjects who are RBC transfusion free over any consecutive 56-day period
    Indipendenza da trasfusioni di globuli rossi (RBCTI) = 8 settimane: proporzione di soggetti liberi da trasfusioni di RBC nell'arco di un periodo di 56 giorni consecutivi
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 1 through Week 24
    Dalla Settimana 1 alla Settimana 24
    E.5.2Secondary end point(s)
    Key secondary endpoint
    1. RBC-TI = 12 weeks - Proportion of subjects who are RBC transfusion free over any consecutive 84-day period
    2. RBC-TI = 8 weeks - Proportion of subjects who are RBC transfusion free over any consecutive 56-day period
    3. Reduction in RBC units transfused over 16 weeks - Mean change in total RBC units transfused over a fixed 16-week period
    4. Modified hematologic improvement - erythroid (mHI-E) per IWG -Proportion of subjects achieving modified HI-E over any consecutive 56-day period
    5. Mean hemoglobin increase = 1.0 g/dL - Proportion of subjects achieving hemoglobin (Hgb) increase from baseline = 1.0 g/dL over any
    consecutive 56-day period in absence of RBC transfusions
    6. Duration of RBC-TI - Maximum duration of RBC transfusion independence for subjects who achieve RBC TI = 8 weeks
    7. Health-related quality of life (HRQoL) - Change in EORTC QLQC30 score
    8. Hematologic improvement - neutrophils (HI-N) / (HI-P) per IWG -Proportion of subjects achieving HI-N / HI-P over any consecutive 56-day period
    9. Mean decrease in serum ferritin - Change in serum ferritin
    10. Mean decrease in iron chelation therapy (ICT) use - Change in mean daily dose of ICT
    11. Time to RBC-TI - Time from first dose to first onset of transfusion independence = 8 weeks
    12. Progression to AML - Number and percentage of subjects progressing to AML; time to AML progression
    13. Overall survival - Time from date of randomization to death due to any cause
    14. Safety - Type, frequency, severity of AEs and relationship of AEs to luspatercept/placebo
    15. A population PK model - A Population PK model that describes the PK exposure data of luspatercept and associated variability.
    16. Exposure-response relationship for the primary efficacy endpoint, AEs of interest, and selected secondary endpoints.
    17. Anti-drug antibodies (ADA) - Frequency of anti-drug antibodies and effects on efficacy, or safety, or PK
    1.RBC-TI = 12 settimane: proporzione di soggetti liberi da trasfusioni di RBC nell'arco di un periodo di 84 giorni consecutivi
    2.RBC-TI = 8 settimane: proporzione di soggetti liberi da trasfusioni di RBC nell'arco di un periodo di 56 giorni consecutivi
    3.Riduzione delle unit¿ di RBC trasfuse nell'arco di 16 settimane: variazione media del totale di unit¿ di RBC trasfuse nell'arco di un periodo fisso di 16 settimane
    4.Miglioramento ematologico-eritroide (mHI-E) modificato secondo IWG: proporzione di soggetti che raggiungono un HI-E modificato nell'arco di un periodo di 56 giorni consecutivi
    5.Aumento medio dell'emoglobina = 1,0 g/dl: proporzione di soggetti che raggiungono un aumento dell'emoglobina (Hgb) dalla baseline = 1,0 g/dl nell'arco di un periodo di 56 giorni consecutivi in assenza di trasfusioni RBC
    6.Durata della RBC-TI: durata massima dell'indipendenza da trasfusioni di RBC per soggetti che raggiungono la RBC-TI = 8 settimane
    7.Qualit¿ di vita correlata allo stato di salute (HRQoL): variazione del punteggio EORTC QLQC30
    8.Miglioramento ematologico-neutrofili (HI-N)/(HI-P) secondo IWG: proporzione di soggetti che raggiungono un HI-N/HI-P nel corso di un qualsiasi periodo di 56 giorni consecutivi
    9.Diminuzione media della ferritina nel siero: variazione della ferritina nel siero
    10.Diminuzione media dell'uso di terapie ferrochelanti (ICT): variazione della dose giornaliera mediadi ICT
    11.Tempo alla RBC-TI: tempo trascorso dalla prima dose alprimo episodio di indipendenza da trasfusioni = 8 settimane
    12.Progressione ad AML: numero e percentuale di soggetti con progressione adAML; tempo alla progressione ad AML
    13.Sopravvivenza complessiva: tempo trascorso dalla data di randomizzazione alla data del decesso per qualsiasi causa
    14.Sicurezza: tipo, frequenza, gravit¿ degli AE e correlazione tra AE e luspatercept/placebo
    15.Modello PK di popolazione: un modello PK di popolazione che descrive i dati di esposizione PK di luspatercept e la variabilit¿ associata.
    16.Correlazione esposizione-risposta per endpoint di efficacia primario, AE di interesse ed selezionati endpoint secondari.
    17.Anticorpi anti-farmaco (ADA): frequenza degli anticorpi anti-farmaco ed effetti su efficacia o sicurezza o PK
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Week 1 to Week 24; Week 1 to Week 48
    2. Week 1 to Week 48
    3. Week 9 to 24; Week 33 to 48
    4+5. Week 1 to Week 24; Week 1 to Week 48
    6. Week 1 to Week 24; Week 1 to end of treatment
    7. Week 1 to Week 24; Baseline to end of treatment
    8. Week 1 to Week 24; Week 1 to Week 48
    9+10. Week 9 to 24; Week 33 to 48
    11. Week 1 to Week 24; Week 1 to Week 48
    12+13. Randomization to at least 3 years post last dose; Week 1 to Week 48
    14. Screening to 42 days post last dose; Week 1 to Week 48
    15+16. Randomization to end of treatment
    17. Randomization to end of treatment; if positive, every 12 weeks for up to 1 year or until return to baseline, whichever comes first
    1.Dalla Settimana 1 alla Settimana 24; dalla Settimana 1 alla Settimana 48
    2.Dalla Settimana 1 alla Settimana 48
    3.Dalla Settimana 9 alla 24; dalla Settimana 33 alla 48
    4+5.Dalla Settimana 1 alla Settimana 24; dalla Settimana 1 alla Settimana 48
    6.Dalla Settimana 1 alla Settimana 24; dalla Settimana 1 alla fine del trattamento
    7.Dalla Settimana 1 alla Settimana 24; dalla baseline alla fine del trattamento
    8.Dalla Settimana 1 alla Settimana 24; dalla Settimana 1 alla Settimana 48
    9+10.Dalla Settimana 9 alla 24; dalla Settimana 33 alla 48
    11.Dalla Settimana 1 alla Settimana 24; dalla Settimana 1 alla Settimana 48
    12+13.Dalla randomizzazione ad almeno 3 anni dopo l'ultima dose; dalla Settimana 1 alla Settimana 48
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA58
    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
    Canada
    Israel
    Russian Federation
    Turkey
    United States
    Belgium
    France
    Germany
    Italy
    Netherlands
    Spain
    Sweden
    United Kingdom
    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
    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 and/or SAP, whichever is the later date.
    Sia 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, dato necessario per l'analisi primaria, secondaria e/o esplorativa, come preliminarmente specificato nel protocollo e/o nel piano di analisi statistica, a seconda di quale delle due date sia l'ultima.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days14
    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: 44
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 185
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 193
    F.4.2.2In the whole clinical trial 229
    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 from treatment for any reason will be followed via telephone contact by the site for collection of data on survival, cause(s) of death, progression to AML, post-treatment therapy(ies) for MDS at the 42-Day and 12-Week Follow-up assessments and then every 3 months after the 12 Week Follow-up assessment for at least 3 years after last dose of IP or until death, lost to follow-up or withdrawal of consent from the study.
    I sogg che interrompono il tratt per qualsiasi ragione saranno seguiti attraverso il contatto telefonico da parte del centro ai fini della raccolta di dati di sopravviv, della causa/e del decesso, della progressione ad AML, della terapia/e post-tratt per MDS tramite valutazioni di follow-up al Giorno 42 e alla Settimana 12, poi ogni 3 mesi dopo la valutazione di follow-up alla Settimana 12 per almeno 3 anni dopo l'ultima dose di IP o fino a decesso, mancata presenza al fu o ritiro del consenso.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-04-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-03-14
    P. End of Trial
    P.End of Trial StatusCompleted
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