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    Summary
    EudraCT Number:2020-004899-18
    Sponsor's Protocol Code Number:LUSPLUS
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-09-07
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2020-004899-18
    A.3Full title of the trial
    A phase IIIb, open-label, single arm study to evaluate the efficacy and safety of luspatercept in patients with lower-risk MDS and ring-sideroblastic phenotype (MDS-RS)
    Estudio de fase IIIb, abierto, de un solo brazo para investigar la eficacia y seguridad de luspatercept en pacientes con SMD de bajo riesgo y con fenotipo sideroblástico en anillo (SMD-SA).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Determination of the effectiveness and safeness of the drug luspatercept in patients who suffering from a low risk type of cancer when blood-forming cells in the bone marrow become abnormal and having characterized by decreased red blood cells below normal.
    Determinación de la eficacia y seguridad del fármaco luspatercept en pacientes que padecen un tipo de cáncer de bajo riesgo cuando las células formadoras de sangre en la médula ósea se vuelven anormales y se caracterizan por una disminución de los glóbulos rojos por debajo de lo normal.
    A.4.1Sponsor's protocol code numberLUSPLUS
    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 SponsorGWT-TUD GmbH
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCelgene International II Sàrl.
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGWT-TUD GmbH
    B.5.2Functional name of contact pointMartin Puttrich
    B.5.3 Address:
    B.5.3.1Street AddressFreiberger Str. 33
    B.5.3.2Town/ cityDresden
    B.5.3.3Post code01067
    B.5.3.4CountryGermany
    B.5.4Telephone number004935125933193
    B.5.5Fax number004935125933198
    B.5.6E-mailmartin.puttrich@g-wt.de
    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® 25 mg
    D.2.1.1.2Name of the Marketing Authorisation holderBristol Myers Squibb Pharma EEIG
    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/3/14/1331
    D.3 Description of the IMP
    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 CodeSUB189400
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product 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® 75 mg
    D.2.1.1.2Name of the Marketing Authorisation holderBristol Myers Squibb Pharma EEIG
    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/3/14/1331
    D.3 Description of the IMP
    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.3.9.2Current sponsor codeACE-536
    D.3.9.3Other descriptive name1373715-00-4
    D.3.9.4EV Substance CodeSUB189400
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product 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
    Lower-risk myelodysplastic syndrome with ring-sideroblastic phenotype (MDS-RS)
    Síndrome mielodisplásico de bajo riesgo y con fenotipo sideroblástico en anillo (SMD-SA).
    E.1.1.1Medical condition in easily understood language
    Patients whose suffering from low risk blood cancer characterized by decreased red blood cells below normal.
    Pacientes que tienen un cáncer de sangre que se caracteriza por una disminución de las células rojas por debajo de lo habitual
    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 21.0
    E.1.2Level LLT
    E.1.2Classification code 10028534
    E.1.2Term Myelodysplastic syndrome NOS
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10068361
    E.1.2Term MDS
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10050910
    E.1.2Term Bone marrow disorder NOS
    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
    The primary objective of the study is to evaluate red blood cell transfusion independence (RBC-TI) rate of luspatercept for the treatment of anemia due to International Prognostic Scoring System-Revised (IPSS-R) very low-, low-, or intermediate-risk MDS in subjects with ring sideroblasts (RS) who require RBC transfusions (according to IWG 2018 criteria)
    El objetivo primario del estudio es evaluar el tiempo en que no se requieren transfusiones de concentrados globulares (RBC-TI) de luspatercept para el tratamiento de la anemia debida al Sistema Prónostico Internacional (IPSS-R) de riesgo muy bajo, bajo o intermedio de SMD en sujetos con sideroblastos en anillo (SA) que requieren transfusiones de glóbulos rojos (según los criterios del IWG 2018)
    E.2.2Secondary objectives of the trial
    • To determine response rates in MDS-RS failing prior therapy with either lenalidomide (LEN) or hypomethylating agents (HMA) according to IWG 2018 criteria (max. 10 patients)
    • To determine RBC-TI and response rates according to IWG 2006 criteria
    • To evaluate the effect of luspatercept on: time to RBC-TI, duration of RBC-TI, increase in hemoglobin (Hb), neutrophils and platelets, decrease in serum ferritin and in iron chelation therapy (ICT) use
    • To investigate safety and tolerability of the luspatercept dosing regimen applied in this study
    • To investigate and compare Quality of Life (QoL) by patient-reported outcome (PRO) and performance outcome (PerfO) measures before and during luspatercept treatment
    • Determinar las tasas de respuesta en los SMD-SA que no hayan recibido tratamiento previo con lenalidomida (LEN) o agentes hipometilantes (HMA) según los criterios del IWG 2018 (máx. 10 pacientes).
    • Determinar RBC-TI y las tasas de respuesta según los criterios del IWG 2006[2].
    • Evaluar el efecto .de luspatercept sobre: el tiempo hasta el RBC-TI, la duración del RBC-TI, el aumento de la hemoglobina (Hb), de los neutrófilos y las plaquetas, la disminución de la ferritina sérica y el uso de quelantes del hierro (ICT).
    • Investigar la seguridad y la tolerabilidad del régimen de dosificación de luspatercept aplicado en este estudio.
    • Investigar y comparar la calidad de vida (QoL) mediante medidas de resultados comunicados por los pacientes (PRO) y de resultados de rendimiento (PerfO) antes y durante el tratamiento con luspatercept.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Principal inclusion criteria

    1. Subject is 18 years of age or older at the time of signing the informed consent form (ICF)

    2. Subject is able to understand and voluntarily sign the ICF prior to any study-related assessments/procedures being conducted

    3. Subject has documented diagnosis of MDS according to WHO classification that meets IPSS-R classification[4] of very low-, low-, or intermediate-risk disease, and the following:
    • Ring sideroblasts (RS) ≥ 15% of erythroid precursors in bone marrow or ≥ 5% if SF3B1 mutation is present
    • Less than 5% blasts in bone marrow
    • Peripheral blood white blood cell (WBC) count < 13,000/μL

    4. Subject must be one of the following:
    • Refractory to prior ESA treatment: Documentation of non-response or response that was no longer maintained to prior ESA-containing regimen, either as a single agent or in combination (e.g. with
    granulocyte colony-stimulating factor [G-CSF]). The ESA regimen must be either:
    - Recombinant human erythropoietin ≥ 40,000 IU/week for at least 8 weeks (=doses) or equivalent; or
    - Darbepoetin-α ≥ 500 μg q3w for at least 4 doses or equivalent
    • Intolerant to prior ESA treatment: Documentation of discontinuation of prior ESA containing regimen, either as a single agent or in combination (e.g. with G-CSF), at any time after introduction due to intolerance or an adverse event (AE)
    • ESA ineligible: Low chance of response to ESA based on endogenous serum erythropoietin (EPO) level > 200 U/L for subjects not previously treated with ESAs
    • Refractory to- /relapsed after prior HMA treatment1: Treatment failure/relapse after at least six (azacitidine) or four (decitabine) 4-week treatment cycles except for del(5q) MDS
    • Refractory to- /relapsed after prior lenalidomide treatment1 except for del(5q) MDS

    5. If previously treated with ESAs or G-CSF/granulocyte-macrophage colony-stimulating factor (GM-CSF), both agents must be discontinued ≥ 4 weeks prior to the date of starting treatment with the Investigational medicinal Product (IMP) in this study

    6. Required RBC transfusions, as documented by the following criteria:
    • Average transfusion requirement of ≥ 2 units/8 weeks of packed RBCs confirmed for a minimum period of 16 weeks immediately preceding start of treatment with IMP
    • Hemoglobin (Hb) levels at the time of or within 7 days prior to administration of an RBC transfusion must be ≤ 10.0 g/dL in order for the transfusion to be counted towards meeting eligibility criteria.
    RBC transfusions administered when Hb levels are > 10 g/dL and/or RBC transfusions administered for elective surgery do not qualify as a required transfusion for the purpose of meeting eligibility criteria
    • No consecutive 56-day period that is RBC transfusion-free during the 16 weeks immediately prior to starting treatment with IMP

    7. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2

    8. A female of childbearing potential (FCBP) for this study is defined as a sexually mature woman who: (1) has not undergone a hysterectomy or bilateral oophorectomy; or (2) is not naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e. had menses at any time in the preceding 24 consecutive months). An FCBP participating in the study must:
    • Have 2 negative pregnancy tests as verified by the investigator prior to starting IMP (unless the screening pregnancy test is done within 72 hours of Cycle 1 Day 1). She must agree to ongoing
    pregnancy testing during the course of the study and after end of treatment (EOT).
    • If sexually active, agree to use, and be able to comply with, highly effective contraception** without interruption, 5 weeks prior to starting IMP, during treatment with IMP (including dose interruptions), and for 12 weeks after discontinuation of IMP.
    ** Highly effective contraception is defined in this protocol as the following (information also appears in the ICF): Hormonal contraception (e.g. birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device, tubal ligation, or a partner with a vasectomy

    9. Male subjects must agree to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (e.g. polyurethane), during sexual contact with a pregnant female or an FCBP while participating in the study, during dose interruptions, and for at least 12 weeks following IMP 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.El sujeto tiene 18 años o más en el momento de firmar el formulario de consentimiento informado (CI)
    2.El sujeto es capaz de entender y firmar voluntariamente el CI antes de que realizar cualquier evaluación/procedimiento del estudio
    3.El sujeto con diagnóstico documentado de SMD según la clasificación de la OMS que cumple la clasificación IPSS-R de enfermedad de riesgo muy bajo, bajo o intermedio, y lo siguiente:
    -Sideroblastos en anillo (SA) ≥ 15% de los precursores eritroides en la médula ósea o ≥ 5% si está presente la mutación SF3B1. Menos del 5% de blastos en la médula ósea
    -Recuento de glóbulos blancos (RGB) en sangre periférica < 13.000/μL
    4.El sujeto debe ser uno de los siguientes:
    -Refractario al tratamiento previo con AEE: historial previo de falta de respuesta o respuesta no sostenida con régimen anterior que contenía AEE, ya sea como agente único o en combinación (por ejemplo, con factor estimulante de colonias de granulocitos [G-CSF]). El régimen de AEE debe ser:
    -Eritropoyetina humana recombinante ≥ 40.000 UI/semana durante al menos 8 semanas (=dosis) o equivalente; o
    -Darbepoetina-α ≥ 500 µg q3w durante al menos 4 dosis o equivalente.
    -Intolerancia al tratamiento previo con AEE: historial previo de la interrupción del régimen anterior que contenía AEE, como agente único o en combinación (por ejemplo, con G-CSF), en cualquier momento después de la introducción debido a la intolerancia o a un evento adverso (EA)
    -No apto para recibir AEE: Baja probabilidad de respuesta a los AEE según el nivel de eritropoyetina sérica endógena> 200 U/L para sujetos no tratados previamente con AEE
    -Refractario a / recaída después de un tratamiento previo con HMA: Fracaso del tratamiento/recaída después de al menos 6 (azacitidina) o 4 (decitabina) ciclos de tratamiento de 4 semanas, excepto para los SMD del(5q).
    -Refractario a/recaída después de un tratamiento previo con lenalidomida1 excepto para los SMD del(5q).
    5.Si se ha tratado previamente con AEE o G-CSF/factor estimulante de colonias de granulocitos-macrófagos (GM-CSF), ambos agentes deben suspenderse ≥ 4 semanas antes de la fecha de inicio del tratamiento con el medicamento en investigación (MEI) en este estudio
    6.Necesidad de transfusiones de glóbulos rojos, según los siguientes criterios:
    -Necesidad media de transfusión de ≥ 2 unidades/8 semanas de glóbulos rojos envasados confirmada durante un período mínimo de 16 semanas inmediatamente anteriores al inicio del tratamiento con el MEI
    -Los niveles de hemoglobina (Hb) en el momento de la transfusión de glóbulos rojos, o en los 7 días anteriores, deben ser ≤ 10,0 g/dl para que la transfusión se contabilice para cumplir los criterios de elegibilidad. Las transfusiones de glóbulos rojos administradas con niveles de Hb> 10 g/dL y/o para una cirugía electiva no se consideran una transfusión necesaria a efectos de los criterios de elegibilidad
    -Ningún período consecutivo de 56 días sin transfusiones de glóbulos rojos durante las 16 semanas anteriores al inicio del tratamiento con el MEI
    7.Puntuación del Eastern Cooperative Oncology Group (ECOG) de 0, 1 ó 2
    8.Una mujer en edad fértil (MEF) se define como una mujer sexualmente madura que (1) no se ha sometido a una histerectomía u ooforectomía bilateral; o (2) no es naturalmente posmenopáusica (la amenorrea después del tratamiento del cáncer no descarta la posibilidad de tener hijos) durante al menos 24 meses consecutivos (es decir, ha tenido la menstruación en cualquier momento de los 24 meses consecutivos anteriores). Una MEF debe realizar:
    -2 pruebas de embarazo negativas verificadas por el investigador antes de comenzar el MEI (a menos que la prueba de embarazo se realice en las 72 horas alrededor del día 1 del ciclo). Debe aceptar someterse a pruebas de embarazo durante el estudio y después del final del tratamiento
    -Si es sexualmente activa, debe estar de acuerdo en utilizar, y ser capaz de cumplir, un método anticonceptivo altamente efectivo** sin interrupción, 5 semanas antes de comenzar el MEI, durante el tratamiento (incluyendo las interrupciones), y durante 12 semanas después de la interrupción del MEI.
    **La anticoncepción altamente efectiva se define como (la información también aparece en el CI): Anticoncepción hormonal (píldoras anticonceptivas, inyección, implante, parche transdérmico, anillo vaginal…), dispositivo intrauterino, ligadura de trompas o una pareja con vasectomía.
    9.Los sujetos masculinos deben aceptar utilizar un preservativo, definido como un preservativo masculino de látex o un preservativo sin látex NO hecho de membrana natural (animal) (por ejemplo, poliuretano), durante el contacto sexual con una mujer embarazada o una MEF mientras participen en el estudio, durante las interrupciones de la dosis y al menos 12 semanas después de la interrupción, incluso si se ha sometido a una vasectomía con éxito.
    10.El sujeto está dispuesto y es capaz de cumplir con el programa de visitas del estudio y otros requisitos del protocolo.
    E.4Principal exclusion criteria
    Principal exclusion criteria

    1. Prior therapy with disease modifying agents other than HMA or LEN for underlying MDS disease

    2. Previously treated with either luspatercept or sotatercept

    3. Secondary MDS, i.e. MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases

    4. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding
    • Iron deficiency to be determined by local laboratory via serum ferritin ≤ 15 μg/L and additional testing if clinically indicated (e.g. calculated transferrin saturation [iron/total iron binding capacity
    ≤ 20%] or bone marrow aspirate stain for iron)

    5. Prior allogeneic or autologous stem cell transplant

    6. Known history of diagnosis of acute myeloid leukemia (AML)

    7. Use of any of the following within 5 weeks prior to the first dose of the IMP in this study:
    • Anticancer cytotoxic chemotherapeutic agent or treatment
    • Corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to the first dose of IMP for medical conditions other than MDS
    • ICT, except for subjects on a stable or decreasing dose for at least 8 weeks prior to the first dose of IMP
    • Other RBC hematopoietic growth factors (e.g. interleukin [IL]-3)
    • Investigational drug or device, or approved therapy for investigational use. If the half-life of the previous study drug is known, the use of it within 5 times the half-life prior to the first dose of IMP or within 5 weeks, whichever is longer, is excluded

    8. Uncontrolled hypertension, defined as repeated elevations of diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment

    9. Platelet count < 30,000/μL (30 × 10^9/L)

    10. Estimated glomerular filtration rate or creatinine clearance < 40 mL/min

    11. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≥ 3.0 × upper limit of normal
    (ULN)

    12. Total bilirubin ≥ 2.0 × ULN
    • Higher levels are acceptable if these can be attributed to active RBC precursor destruction within the bone marrow (i.e. ineffective erythropoiesis) or in the presence of known history of Gilbert
    Syndrome
    • 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

    13. Prior history of malignancies, other than MDS, unless the subject is free of the disease (including completion of any active or adjuvant treatment for prior malignancy) 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 clinical staging system)

    14. Major surgery within 8 weeks prior to the first dose of IMP. Subjects must be completely recovered from any previous surgery prior to the first dose of IMP

    15. History of stroke, deep venous thrombosis, pulmonary or arterial embolism within 6 months prior to the first dose of IMP

    16. Pregnant or breast-feeding females

    17. Myocardial infarction, uncontrolled angina, uncontrolled heart failure, or uncontrolled cardiac arrhythmia as determined by the investigator within 6 months prior to the first dose of IMP. Subjects with a known ejection fraction of ˂ 35%, confirmed by a local echocardiography or multigated acquisition scan (MUGA) performed within 6 months prior to the first dose of IMP, are excluded

    18. 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), known evidence of active infectious hepatitis B, and/or known evidence of active hepatitis C

    19. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the IMP

    20. Subject is in custody by order of an authority or a court of law

    21. Participation in another interventional clinical study within the last 3 months prior to signing the ICF or simultaneous participation in other clinical studies

    22. Previous assignment to treatment during this study

    23. Close affiliation with the investigator (e.g. a close relative) or persons working at the study site

    24. Subject is an employee of the sponsor or involved Contract research Organization (CRO)

    25. Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the subject’s safety
    1.Terapia previa con agentes modificadores de la enfermedad que no sean HMA o LEN
    2.Tratamiento previo con luspatercept o sotatercept
    3.SMD secundarios, es decir, SMD que se sabe que han surgido como resultado de una lesión química o de un tratamiento con quimioterapia y/o radiación para otras enfermedades
    4.Anemia clínicamente significativa conocida debido a deficiencias de hierro, vitamina B12 o folato, o anemia hemolítica autoinmune o hereditaria, o hemorragia gastrointestinal
    -Deficiencia de hierro a determinar por el laboratorio local mediante ferritina sérica ≤15 µg/L y pruebas adicionales si están clínicamente indicadas (por ejemplo, cálculo de saturación de transferrina[hierro/capacidad total de fijación del hierro ≤ 20%] o tinción de aspiración de hierro en médula ósea).
    5.Trasplante previo de células madre alogénico o autólogo
    6.Antecedentes conocidos de diagnóstico de LMA
    7.Uso de cualquiera de los siguientes en las 5 semanas anteriores a la primera dosis del MEI:
    -Agente o tratamiento quimioterapéutico citotóxico anticanceroso
    -Corticosteroides, excepto para los sujetos en una dosis estable o decreciente durante ≥ 1 semana antes de la primera dosis de MEI por enfermedad distintas de los SMD
    -ICT, excepto para los sujetos que hayan recibido una dosis estable o decreciente durante al menos 8 semanas antes de la primera dosis de MEI
    -Otros factores de crecimiento hematopoyético de los glóbulos rojos (por ejemplo, interleucina [IL]-3)
    -Fármaco o dispositivo en investigación, o terapia aprobada para uso en investigación. Si se conoce la vida media del fármaco del estudio anterior, se excluye el uso del mismo dentro de 5 veces la vida media antes de la primera dosis de MEI o dentro de 5 semanas, lo más largo.
    8.Hipertensión no controlada, definida como elevaciones repetidas de la presión arterial diastólica≥ 100 mmHg a pesar de un tratamiento adecuado
    9.Recuento de plaquetas < 30.000/μL (30×109/L)
    10.Tasa de filtración glomerular estimada o aclaramiento de creatinina
    <40 mL/min
    11.Aspartato aminotransferasa (AST)/transaminasa glutámicooxalacética sérica (SGOT) o alanina aminotransferasa (ALT)/transaminasa glutámica pirúvica sérica (SGPT) ≥ 3,0 × límite superior de la normalidad (ULN)
    12.Bilirrubina total ≥ 2,0×ULN
    -Se aceptan niveles más altos si pueden atribuirse a la destrucción activa de precursores de glóbulos rojos dentro de la médula ósea (eritropoyesis ineficaz) o en presencia de antecedentes conocidos de síndrome de Gilbert
    -Evidencia de anemia hemolítica autoinmune manifestada como un recuento de reticulocitos corregido de > 2% con una prueba de Coombs positiva o más del 50% de bilirrubina indirecta
    13.Antecedentes de enfermedades malignas, excepto SMD, a menos que el sujeto esté libre de la enfermedad (incluyendo la finalización de cualquier tratamiento activo o adyuvante para una enfermedad maligna previa) durante≥ 5 años. Sin embargo, se permiten sujetos con los siguientes antecedentes/condiciones actuales:
    -Carcinoma de células basales o escamosas de la piel
    -Carcinoma in situ del cuello uterino
    -Carcinoma in situ de mama
    -Hallazgo histológico incidental de cáncer de próstata (T1a o T1b según el sistema de estadificación clínica de tumores, ganglios y metástasis)
    14.Cirugía mayor en las 8 semanas anteriores a la primera dosis de MEI. Los sujetos deben estar completamente recuperados de cualquier cirugía previa antes de la primera dosis de MEI.
    15.Antecedentes de accidente cerebrovascular, trombosis venosa profunda, embolia pulmonar o arterial en los 6 meses anteriores a la primera dosis de MEI.
    16.Mujeres embarazadas o en periodo de lactancia
    17.Infarto de miocardio, angina de pecho no controlada, insuficiencia cardíaca no controlada o arritmia cardíaca no controlada, según determine el investigador, en los 6 meses anteriores a la primera dosis de MEI. Quedan excluidos los sujetos con una gammagrafía de adquisición multigenerada (MUGA) conocida realizada en los 6 meses anteriores a la primera dosis de MEI.
    18.Infección sistémica fúngica, bacteriana o viral no controlada (definida como tratamiento), virus de la inmunodeficiencia humana (VIH) conocido, evidencia conocida de hepatitis C activa
    19.Antecedentes de reacciones alérgicas o anafilácticas graves o de hipersensibilidad a las proteínas recombinantes o a los excipientes del MEI.
    20.El sujeto está bajo custodia por orden de una autoridad o de un tribunal
    21.Participación en otro estudio clínico de intervención en los últimos 3 meses anteriores a la firma del CI o participación simultánea en otros estudios clínicos
    22.participacion previa en el estudio
    23. Relación estrecha con el investigador (por ejemplo, un pariente cercano) o con personas que trabajan en el lugar del estudio
    24.El sujeto es un empleado del promotor o de la Organización de Investigación por Contrato (CRO) involucrada
    25.Criterios que, en opinión del investigador, impiden la participación por razones científicas, de cumplimiento o de seguridad del sujeto
    E.5 End points
    E.5.1Primary end point(s)
    RBC-TI rate according to IWG 2018 modified criteria
    Tasa RCB-TI según los criterios modificados desde la semana 1 hasta la semana 24.
    E.5.1.1Timepoint(s) of evaluation of this end point
    from Week 1 through Week 24
    Entre la semana 1 hasta la semana 24
    E.5.2Secondary end point(s)
    • RBC-TI rate according to IWG 2006 criteria from Week 1 through Week 24 and through Week 52
    • Median time to RBC-TI (Week 1 through Week 24 and through Week 52)
    • Median duration of RBC-TI (Week 1 through Week 24 and through Week 52)
    • Change in RBC units transfused over a fixed 16-weeks period (Week 9 through Week 24 and Week 37 through Week 52) compared to the 16-week period prior to screening
    • Proportion of subjects achieving mean Hb increase ≥ 1.0 g/dL over ≥ 8 weeks (Week 1 through Week 24 and through Week 52)
    • Proportion of subjects achieving modified hematologic improvement - erythroids (mHI-E) per IWG 2006 criteria (Week 1 through Week 24 and through Week 52)
    • Proportion of subjects achieving hematologic improvement - neutrophils (HI-N) per IWG 2006 criteria[2] (Week 1 through Week 24 and through Week 52)
    • Proportion of subjects achieving hematologic improvement - platelets (HI-P) per IWG 2006 criteria (Week 1 through Week 24 and through Week 52)
    • Mean change in serum ferritin from Week 9 through 24 and Week 37 through Week 52 compared to baseline
    • Mean change in mean daily dose of ICT from Week 9 through 24 and Week 37 through Week 52 compared to baseline
    • Proportion of subjects with progression to AML
    • Overall survival (OS)
    • Safety measures: type, frequency, severity of adverse events (AEs) and relationship to luspatercept, dose reductions and dose delays
    • Mean change in PRO (via EORTC QLQ-C30) and PerfO (via “Timed Up and Go test” [TUG]) from baseline (Week 1) to Week 52 and to End of Treatment (EOT).
    • Tasa de RBC-TI según los criterios del IWG 2006[2] desde la semana 1 hasta la semana 24 y hasta la semana 52
    • Tiempo medio hasta el RBC-TI (desde la semana 1 a la semana 24 y hasta la semana 52)
    • Duración media de la RBC-TI (desde la semana 1 a la semana 24 y hasta la semana 52)
    • Cambio en las unidades de glóbulos rojos transfundidos durante un período fijo de 16 semanas (de la semana 9 a la 24 y de la 37 a la 52) en comparación con el período de 16 semanas anterior al cribado
    • Proporción de sujetos que logran un aumento medio de Hb ≥ 1,0 g/dL durante ≥ 8 semanas (de la semana 1 a la semana 24 y hasta la semana 52)
    • Proporción de sujetos que logran una mejora hematológica modificada - eritroides (mHI-E) según los criterios del IWG 2006[2] (De semana 1 a la Semana 24 y hasta la Semana 52)
    • Proporción de sujetos que logran una mejoría hematológica - neutrófilos (HI-N) según los criterios del IWG 2006[2] (Semana 1 hasta la Semana 24 y hasta la Semana 52)
    • Proporción de sujetos que logran una mejora hematológica - plaquetas (HI-P) según los criterios del IWG 2006[2] (desde la semana 1 hasta la semana 24 y hasta la semana 52)
    • Cambio medio en la ferritina sérica desde la Semana 9 hasta la 24 y desde la Semana 37 hasta la Semana 52 en comparación con el valor inicial
    • Cambio medio en la dosis diaria media de ICT de la semana 9 a la 24 y de la semana 37 a la 52 en comparación con el valor inicial
    • Proporción de sujetos con progresión a leucemia mieloide aguda (LMA)
    • Supervivencia global (SG)
    • Medidas de seguridad: tipo, frecuencia, gravedad de los acontecimientos adversos (AAs) y relación con el luspatercept, reducciones y retrasos de dosis
    • Cambio medio en PRO (a través de EORTC QLQ-C30) y PerfO (a través de "Timed Up and Go test" [TUG]) desde el inicio (Semana 1) hasta la Semana 52 y hasta el final del tratamiento (FDT).
    E.5.2.1Timepoint(s) of evaluation of this end point
    as mentioned above in 5.2
    segun lo mencionado en el punto 5.2
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA14
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Switzerland
    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
    As for this study, the primary outcome will be analyzed after the last patient has completed the study (individual EOS). The end of the study as a whole will be the date when the clean database is available and ready for export for the statistical analyses. However, the primary completion event of the study will be the date of last patient end of study (LPEOS).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    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: 35
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 35
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 62
    F.4.2.2In the whole clinical trial 70
    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)
    If a patient benefits from the treatment applied in this study, luspatercept dosing might be continued beyond the end of this study at the discretion of the treating physician.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation European Myelodysplastic Syndromes Cooperative Group
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-12-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-12-05
    P. End of Trial
    P.End of Trial StatusOngoing
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