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    Summary
    EudraCT Number:2016-000704-28
    Sponsor's Protocol Code Number:GCP#05.01.020
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-10-01
    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 ConcernedPortugal - INFARMED
    A.2EudraCT number2016-000704-28
    A.3Full title of the trial
    A Multicenter, Randomized, Phase III Registration Trial of Transplantation of NiCord®, Ex Vivo Expanded, Umbilical Cord Blood-derived, Stem and Progenitor Cells, versus Unmanipulated Umbilical Cord Blood for Patients with Hematological Malignancies
    Ensaio de registo de fase III, aleatorizado e multicêntrico de transplante de células estaminais e progenitoras derivadas do sangue do cordão umbilical, expandidas ex vivo NiCord® versus sangue do cordão umbilical não manipulado para pacientes com doenças malignas do sangue.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multicenter trial of transplantation of NiCord, stem cells from donated umbilical cord blood that were grown in a laboratory to expand their number versus unmanipulated umbilical cord blood for patients with cancers of the blood and lymph
    Um estudo multicêntrico de transplante de NiCord, células estaminais provenientes de sangue do cordão umbilical doado que foram cultivadas em laboratório para expandir o seu número vs. sangue do cordão umbilical não manipulado em pacientes com cancro do sangue e cancro linfático
    A.4.1Sponsor's protocol code numberGCP#05.01.020
    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 SponsorGamida Cell Ltd
    B.1.3.4CountryIsrael
    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 supportGamida Cell Ltd
    B.4.2CountryIsrael
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGamida Cell Ltd
    B.5.2Functional name of contact pointClinical trial department
    B.5.3 Address:
    B.5.3.1Street Address5, Nahum Hafzadi, Beit Ofer
    B.5.3.2Town/ cityJerusalem
    B.5.3.3Post code9548401
    B.5.3.4CountryIsrael
    B.5.4Telephone number97226595666
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/17/1852
    D.3 Description of the IMP
    D.3.1Product nameNiCord (CF cultured fraction and NF non-cultured fraction)
    D.3.4Pharmaceutical form Dispersion for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAllogeneic, ex vivo expanded, umbilical cord blood-derived, hematopoietic CD34+ progenitor cells
    D.3.9.3Other descriptive nameALLOGENEIC, EX VIVO EXPANDED, UMBILICAL CORD BLOOD-DERIVED, HEMATOPOIETIC CD34+ PROGENITOR CELLS
    D.3.9.4EV Substance CodeSUB181698
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number800000000
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAllogeneic, non-expanded, umbilical cord blood-derived, hematopoietic mature myeloid and lymphoid cells
    D.3.9.3Other descriptive nameALLOGENEIC, NON-EXPANDED, UMBILICAL CORD BLOOD-DERIVED, HEMATOPOIETIC MATURE MYELOID AND LYMPHOID CELLS
    D.3.9.4EV Substance CodeSUB181699
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number400000000
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    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
    High risk haematological malignancies
    Neoplasias hematológicas de alto riesgo
    E.1.1.1Medical condition in easily understood language
    cancer affecting blood, bone marrow, lymph nodes
    câncer que afeta sangue, medula óssea, gânglios linfáticos
    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 10000845
    E.1.2Term Acute lymphoblastic leukemia
    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 10000886
    E.1.2Term Acute myeloid leukemia
    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 10009015
    E.1.2Term Chronic myeloid leukemia
    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 10028534
    E.1.2Term Myelodysplastic syndrome NOS
    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 10006597
    E.1.2Term Burkitt's lymphoma NOS
    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 10076434
    E.1.2Term Hepatosplenic gamma-delta T-cell lymphoma
    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 10025315
    E.1.2Term Lymphoma malignant
    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 10036889
    E.1.2Term Prolymphocytic leukemia
    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 10073481
    E.1.2Term Enteropathy-associated T-cell lymphoma
    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 10054481
    E.1.2Term Natural killer-cell leukemia
    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 10054655
    E.1.2Term T-cell type acute leukemia
    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 10000836
    E.1.2Term Acute leukemia NOS
    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 10067837
    E.1.2Term Acute biphenotypic leukemia
    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 10054681
    E.1.2Term Undifferentiated type acute leukemia
    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 10054350
    E.1.2Term Chronic myelomonocytic leukemia
    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
    The overall study objective is to compare the safety and efficacy of NiCord single ex-vivo expanded cord blood unit transplantation to unmanipulated cord blood unit transplantation in patients with hematological malignancies following conditioning therapy
    O objetivo geral do estudo é comparar a segurança e a eficácia de um único transplante
    de unidades de sangue do cordão umbilical expandidas ex vivo NiCord® com as do
    transplante de unidades de sangue do cordão umbilical não manipuladas em pacientes
    com doenças malignas do sangue após terapia de condicionamento
    E.2.2Secondary objectives of the trial
    Not applicable - see primary and secondary endpoints sections
    Não aplicável - consulte as secções sobre endpoints primários e secundários
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1. Optional Long term follow-up sub-study- For patients who received transplantation and agreed to enroll in the observational long term follow-up sub-study, long-term outcomes will be collected at 2 years, 3 years, 4 years and 5 years post transplantation.
    The overall research goals for this sub-study are:
    -Describe long term sustained donor chimerism
    -Describe survival and disease free survival
    -Describe characteristics of patients with secondary graft failure or disease relapse
    -Describe long term immune reconstitution
    -Describe incidence of chronic GvHD
    2.Optional supplemental immune reconstitution sub-study will
    explore immune biomarkers potentially predicting clinical outcomes such as relapse, engraftment and viral reactivation/disease. Blood samples for exploratory research of immune reconstitution will be collected from the patients who consent to this sub-study for immunophenotyping and MultiPlex analyses (on days 7, 14, 21, 28, 42, 56, 70, 100, 180, and day 365 visits) as well as for T cell receptor analysis (at screening and on days 100, 180 and 365 visits). These samples will be sent to a central laboratory for analysis as detailed in a separate research study plan.
    1. Estudo secundário de seguimento a longo prazo opcional - No caso dos pacientes que receberam transplante e concordaram em se inscrever no estudo secundário empírico de seguimento a longo prazo, os resultados a longo prazo serão recolhidos aos 2 anos, 3 anos, 4 anos e 5 anos após o transplante.
    Os objetivos globais de investigação deste subestudo são:
    - Descrever o quimerismo do doador sustentado a longo prazo
    - Descrever a sobrevivência e a sobrevivência geral à doença
    - Descrever as características dos pacientes com insucesso secundário do enxerto ou recidiva da doença
    - Descrever a reconstituição imunológica a longo prazo
    - Descrever a incidência da DECH crónica
    2. O subestudo complementar de reconstituição imunológica opcional irá explorar biomarcadores imunológicos que potencialmente poderão prever resultados clínicos como recidiva, enxerto e doença/reativação viral. As amostras de sangue para investigação exploratória da reconstituição imunológica serão recolhidas dos pacientes que concordarem em participar neste subestudo para fins de imunofenotipagem e análises MultiPlex (nas consultas dos dias 7, 14, 21, 28, 42, 56, 70, 100, 180 e 365), bem como para análise do recetor de células T (no momento da triagem e nas consultas dos dias 100, 180 e 365). Estas amostras serão enviadas para um laboratório central para fins de análise, conforme detalhado num plano de estudo de investigação separado.
    E.3Principal inclusion criteria
    1.12-65 years of age
    2.Patients with one of the following HM: Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), CMMoL or MDS/CMMoL overlap, Myelodysplastic Syndrome (MDS) and Lymphoma as defined in the protocol. Biphenotypic/undifferentiated/Prolymphocytic/Dendritic Cell
    Leukemias and Natural Killer Cell Malignancies in first or subsequent CR, adult T-cell leukemia/lymphoma in first or subsequent CR. Patients with CLL are not eligible regardless of disease status.
    3.CBU criteria as described in the protocol;
    4.Patients who will be starting conditioning prior to NiCord release for infusion (i.e., NiCord arrival on site in adequate condition) must have an additional partially HLA-matched CBU reserved as a BU to the NiCord arm in case of production failure. The BU CBU must be HLA-matched at 4-6/6 HLA class I(HLA-A&HLA-B, low resolution) and II (HLA-DRB1,high resolution) loci with the patient. A second BU CBU is recommended to be
    added in the below cases: If the BU CBU is HLA matched at 5-or 6/6, and contains a pre-cryopreserved total nucleated cell dose of<2.5x10^7 TNC/kg, OR a pre- cryopreserved CD34+ cell dose
    of<1.2 x10^5CD34+ cells/kg. If the BU CBU is HLA-matched at 4/6, and contains a pre-cryopreserved total nucleated cell dose of<3.5x10^7 TNC/kg, OR a pre cryopreserved CD34+ cell dose of
    <1.7x10^5CD34+cells/kg. In case of two BU CBUs, the second BU CBU must also be HLA-matched at 4-6/6 HLA class I(HLA-A&HLA-B, low resolution) and II (HLA-DRB1,high resolution) loci with the patient. The BU CBUs are recommended to have a combined pre-cryopreserved total nucleated cell dose of at least 3x10^7 TNC/kg.
    5.Patient's Performance score ≥70% by Karnofsky or Lansky
    6. Patient has sufficient physiologic reserves including: a.Cardiac: LVEF of ≥40% by echocardiogram, radionuclide scan or cardiac MRI or Left
    ventricular shortening fraction ≥ 29%. b.PFT demonstrating FVC and FEV1 of >50% of predicted for age and cDLCO>50% of predicted for
    patients in whom pulmonary function testing can be performed c.Renal: Creatinine clearance test ≥60mL/min d.Hepatic: Serum Bilirubin<2.0 mg/dl; Hepatic transaminases<3xupper limit of normal range
    7.Females of childbearing potential, defined as any female who has experienced menarche and is not postmenopausal or permanently sterilized, agree to use an appropriate method of contraception from at least 7 days prior to conditioning regimen therapy until completion of FU procedures.
    8.Patient signs the written informed consent after being aware of the nature of the patient's disease and willingly consents to the treatment program after being informed of alternative treatments, potential risks, benefits, and discomforts
    1. 12 e 65 anos de idade
    2. Pacientes com uma das seguintes doenças: Leucemia linfoblástica aguda (LLA), Leucemia mielogénica aguda (LMA), Leucemia mielogénica crónica (LMC), Sobreposição de LMMC ou SMD/LMMC, Síndrome mielodisplásica (SMD), Leucemias de células bifenotípicas/indiferenciadas/prolinfocíticas/dendríticas e doenças malignas de células Natural Killer aquando da primeira RC ou RC posteriores, leucemia/linfoma de células T em adultos aquando da primeira RC ou RC posteriores Linfoma como esta definido no protocolo

    3. Critérios da USC conforme descritos no protocolo.
    4. Pacientes que iniciarão o condicionamento antes da libertação de NiCord para
    infusão (isto é, chegada de NiCord no local em condições adequadas) devem ter
    uma USC parcialmente compatível com HLA reservada para o grupo de NiCord
    em caso de falha na produção. A USC de reserva deve ser compatível com HLA
    em 4–6/6 localizações de classe I (HLA-A e HLA-B, baixa resolução) e II (HLADRB1, alta resolução) com o paciente. Recomenda-se a adição de uma segunda USC de reserva nos seguintes casos: Se a USC de reserva for compatível com HLA em 5 ou 6/6 e contiver uma dose total de células nucleadas previamente criopreservadas (pósprocessamento) < 2,5x107 CNT/kg OU uma dose de células CD34+ previamente criopreservadas (pós-processamento) de < 1,2x105 células CD34+/kg. Se a USC de reserva for compatível com HLA em 4/6 e contiver uma dose total de células nucleadas previamente criopreservadas (pósprocessamento) < 3,5x107 CNT/kg OU uma dose de células CD34+previamente criopreservadas (pós-processamento) de < 1,7x105 células CD34+/kg. No caso de duas USC de reserva, a segunda USC de reserva também deve ser compatível com HLA em 4–6/6 localizações de classe I (HLA-A e HLA-B, baixa resolução) e II (HLA-DRB1, alta resolução) com o paciente. Recomenda-se que as USC de reserva tenham uma dose combinada de células nucleadas totais previamente criopreservadas (pós-processamento) de pelo menos 3x107 CNT/kg.

    5. Pontuação de desempenho do paciente ≥ 70% por Karnofsky ou Lansky
    6. O paciente tem reservas fisiológicas suficientes, incluindo: a. Cardíacas: FEVE ≥ 40% por ecocardiograma, exame de radionuclídeo ou RMC ou fração de encurtamento ventricular esquerdo ≥ 29%. b.PFT demonstrando CVF e VEF1 de > 50% do previsto para a idade e cDLCO > 50% do previsto no caso de pacientes em que é possível fazer testes da função pulmonar. c. Renais: Teste de depuração de creatinina ≥ 60 ml/min. d. Hepáticos: Bilirrubina sérica < 2,0 mg/dl; transaminases hepáticas< 3 x limite superior da faixa normal

    7. Mulheres com potencial para engravidar, definidas como qualquer mulher que
    tenha tido a menarca e não esteja pós-menopáusica ou permanentemente esterilizada concordam em utilizar um método de contraceção apropriado de pelo menos 7 dias antes da terapia do regime de condicionamento até à conclusão dos procedimentos de seguimento.

    8. O paciente assina o consentimento esclarecido por escrito após ter conhecimento da natureza da doença do paciente e consente voluntariamente com o programa de tratamento após ser informado de tratamentos alternativos, riscos potenciais, benefícios e desconfortos
    E.4Principal exclusion criteria
    1.MDS or CML with “marked” or “3+” fibrosis
    2. CLL
    3.Fewer than 21 days have elapsed since initiation of the patient's last chemotherapy cycle and the initiation of the stem cell transplant preparative regimen (radiotherapy,intrathecal agents, hydroxyurea, tyrosine kinase inhibitors, hypomethylating agents, rituximab, blinatumomab and lenalidomide are not considered chemotherapy)
    4.Persistent clinically significant toxicities that, in the investigator's opinion, make the patient unsuitable for transplant
    5.Evidence of donor specific anti-HLA antibodies to the selected treatment CBU #1 (MFI>3000 to HLA A, B, C, or DRB1)
    6.Evidence of HIV infection or HIV positive serology
    7.Evidence of active Hepatitis B or Hepatitis C as determined by serology or PCR
    8.Pregnancy, as indicated by a positive serum or urine human chorionic gonadotrophin (HCG) test, or lactation
    9.Active malignancy other than that for which the UCB transplant is being performed within 12 months of enrollment. Fully resected cutaneous squamous cell or basal cell carcinoma or cervical carcinoma in situ within 12 months of enrollment will be permitted.
    10.Evidence of uncontrolled bacterial, fungal or viral infections or severe concomitant diseases, which in the judgment of the Principal investigator indicate that the patient could not tolerate transplantation
    11.Patients with presence of leukemic blasts in the central nervous system (CNS)
    12.Patients with an 8/8 allele level HLA-matched and readily available related or unrelated donor (whose stem cells can be collected in a timely manner without jeopardizing recipient outcome). Patients who have haploidentical related donors or syngeneic donors will not be excluded
    13.Prior allogeneic hematopoietic stem cell transplant
    14.Allergy to bovine products, gentamicin, or to any other product that may interfere with the treatment
    15.Psychologically incapable of undergoing bone marrow transplant (BMT) with associated strict isolation or documented history of medical non-compliance and/or psychiatric illness and/or social situations that would limit compliance with study requirements
    16.Enrolled in another interventional clinical trial or received an investigational treatment within 30 days prior to the approved date of randomization, unless documented approval obtained from Sponsor prior to the anticipated date of randomization, unless documented approval obtained from Sponsor prior to randomization
    1. SMD ou LMC com fibrose "significativa" ou "3+"
    2. LLC
    3. Decorreram menos de 21 dias desde o início do último ciclo de quimioterapia do paciente e o início do regime de preparação para o transplante de células
    estaminais (radioterapia, agentes intratecais, hidroxiureia, inibidores da tirosina quinase, agentes hipometilantes, rituximabe, blinatumomab e lenalidomida não são considerados quimioterapia)
    4. Toxicidade clinicamente significativa e persistente que, na opinião do investigador, torna o paciente inadequado para transplante
    5. Evidência de anticorpos anti-HLA específicos do doador para o tratamento selecionado com USC n.º 1 (IFM > 3000 para HLA A, B, C ou DRB1)
    6. Evidência de infeção por VIH ou sorologia positiva para VIH
    7. Evidência de hepatite B ou hepatite C ativa, conforme determinado por sorologia
    ou RCP
    8. Gravidez, conforme indicado por um teste de gonadotrofina coriónica humana (GCH) sérico ou urinário positivo ou lactação
    9. Doença maligna ativa diferente daquela para a qual o transplante de SCU está a ser realizado dentro de 12 meses após a inclusão. Será permitido carcinoma de células escamosas ou basal cutâneo totalmente ressecado ou carcinoma cervical in situ em 12 meses após a inclusão.
    10. Evidência de infeções bacterianas, fúngicas ou virais não controladas ou doenças
    concomitantes graves, que, no parecer do investigador principal, indicam que o
    paciente não poderia tolerar o transplante
    11. Pacientes com presença de blastos leucémicos no sistema nervoso central (SNC)
    12. Pacientes com um nível de alelo de 8/8 compatível com HLA e doador imediatamente disponível relacionado ou não relacionado (cujas células estaminais podem ser recolhidas rapidamente sem comprometer o resultado do
    recetor). Os pacientes que possuem doadores relacionados haploidênticos ou singeneicos não serão excluídos
    13. Transplante de células estaminais hematopoiéticas alogénicas anterior
    14. Alergia a produtos bovinos, gentamicina ou a qualquer outro produto que possa interferir no tratamento
    15. Psicologicamente incapaz de se submeter a transplante de medula óssea (TMO)
    com isolamento estrito associado ou histórico documentada de não conformidade médica e/ou doença psiquiátrica e/ou situações sociais que limitariam a conformidade com os requisitos do estudo
    16. Foi incluído noutro ensaio clínico intervencionista ou recebeu um tratamento
    experimental dentro de 30 dias antes da data prevista de aleatorização, salvo aprovação documentada obtida do Patrocinador antes da aleatorização
    E.5 End points
    E.5.1Primary end point(s)
    Assess the time to neutrophil engraftment following transplantation.
    Neutrophil engraftment is defined as achieving an absolute neutrophil count (ANC) ≥ 0.5 x 10^9/L on 3 consecutive measurements on different days with subsequent donor chimerism (≤10% host cells by peripheral blood chimerism or bone marrow chimerism if peripheral blood chimerism is not available). The day of neutrophil engraftment is designated as the first of the 3 consecutive measurements and must occur on or before 42 days post transplant (and also prior to infusion of any additional stem cell product).
    Avaliar o tempo até ao enxerto de neutrófilos após o transplante.
    Enxerto de neutrófilos define-se como alcançar uma contagem absoluta de neutrófilos (CAN) ≥ 0,5 x 10^9/L em três medições consecutivas em dias diferentes com posterior quimerismo do doador (≤ 10% de células hospedeiras por quimerismo de sangue periférico ou quimerismo de medula óssea se não estiver disponível quimerismo de sangue periférico). O dia do enxerto de neutrófilos é designado como a primeira das três medições consecutivas e deve ocorrer até 42 dias após o transplante (e também antes da infusão de qualquer produto adicional de células estaminais).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Not relevant
    Não é relevante
    E.5.2Secondary end point(s)
    Secondary Endpoints:
    •Incidence of grade 2/3 bacterial or invasive fungal infections by 100 days following transplantation
    •Days alive and out of hospital in the first 100 days following transplantation
    •Platelet engraftment by 42 days following transplantation
    Tertiary Endpoint:
    •Non-relapse mortality by 210 days following randomization
    Exploratory Endpoints:
    •Neutrophil engraftment by 16 days following transplantation
    •Time from transplantation to platelet engraftment
    •Duration of primary hospitalization
    •Non-relapse mortality by 130 days and 15 months following randomization
    •Overall survival at 210 days and 15 months following randomization
    •Disease-free survival at 15 months following randomization
    •Neutrophil engraftment by 42 days following transplantation
    •Acute GvHD grade II-IV and III-IV by 100 days following transplantation
    •Chronic GvHD (mild/moderate/severe) by 180 days and 1 year following transplantation
    •Secondary graft failure by 1 year following transplantation
    •Grade 3 viral infections by 180 days and 1 year following transplantation
    •Safety and tolerability of NiCord® transplantation
    •Relapse by 15 months following randomization
    •Relapse mortality by 15 months following randomization
    •Immune reconstitution at 28, 70, 100, 180, and 365 days following transplantation
    •Supplemental immune reconstitution assessments at a central
    laboratory (optional)
    •Health-related quality of life
    •Long-term clinical outcomes up to 5 years following transplantation (optional)
    Endpoints secundários:
    • Incidência de infeções bacterianas ou invasivas de grau 2/3 durante 100 dias
    após o transplante
    • Dias com vida e fora do hospital nos primeiros 100 dias após o transplante
    • Enxerto de plaquetas 42 dias após o transplante
    Endpoint terciário:
    • Mortalidade não recidivante 210 dias após a aleatorização
    Endpoints exploratórios:
    • Enxerto de neutrófilos 16 dias após o transplante
    • Tempo do transplante até ao enxerto de plaquetas
    • Duração da hospitalização primária
    • Mortalidade não recidivante 130 dias e 15 meses após a aleatorização
    • Sobrevivência geral 210 dias e 15 meses após a aleatorização
    • Sobrevivência geral à doença 15 meses após a aleatorização
    • Enxerto de neutrófilos 42 dias após o transplante
    • DECH aguda de grau II–IV e III–IV 100 dias após o transplante
    • DECH crónica (leve/moderada/grave) 180 dias e 1 ano após o transplante
    • Insuficiência do enxerto secundário 1 ano após o transplante
    • Infeções virais de grau 3 180 dias e 1 ano após o transplante
    • Segurança e tolerabilidade do transplante de NiCord®
    • Recidiva 15 meses após a aleatorização
    • Mortalidade por recidiva 15 meses após a aleatorização
    • Reconstituição imunológica 28, 70, 100, 180 e 365 dias após o transplante
    • Avaliações complementares da reconstituição do sistema imunitário num laboratório central (opcional)
    • Qualidade de vida relacionada com a saúde
    • Resultados clínicos a longo prazo até 5 anos após o transplante (opcional)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary EP
    day 100 following transplantation
    day 100 following transplantation
    day 42 following transplantation
    Tertiary EP
    day 210 following randomization
    Exploratory EP
    day 16 following transplantation
    NR
    NR
    day 130 and 15mon. following random.
    day 210 and 15mon. following random.
    15 mon. following randomi.
    day 42 following transplant
    day 100 following transplant
    day 180 and 1 year following transplant
    1 year following transplantation
    day 180 and 1 year following transplant
    NR
    15mon. following random.
    15mon. following random.
    day 28, 70, 100, 180 &365 following transplant
    MultiPlex analyses (days 7, 14, 21, 28, 42, 56, 70, 100, 180 &day 365 visits and T cell receptor analysis (at screening and on days 100, 180 and 365 visits)
    NR
    2,3,4&5 years post transplantat
    EP secundário
    dia 100 após o transplante
    dia 100 após o transplante
    dia 42 após o transplante
    EP terciário
    dia 210 após a aleatorização
    EP exploratório
    dia 16 após o transplante
    NR
    NR
    dia 130 e 15 meses após a aleatorização
    dia 210 e 15 meses após a aleatorização
    15 meses após a aleatorização
    dia 42 após o transplante
    dia 100 após o transplante
    dia 180 e 1 ano após o transplante
    1 ano após o transplante
    dia 180 e 1 ano após o transplante
    NR
    15 meses após a aleatorização
    15 meses após a aleatorização
    dia 28, 70, 100, 180 e 365 após o transplante
    Análises MultiPlex (consultas dos dias 7, 14, 21, 28, 42, 56, 70, 100, 180 e 365 e análise do recetor de células T (no momento da triagem e nas consultas dos dias 100, 180 e 365)
    NR
    2, 3, 4 e 5 anos após o transplante
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) 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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    one or two Unmanipulated Umbilical Cord Blood Unit(s)
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA 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
    Brazil
    France
    Israel
    Italy
    Netherlands
    Portugal
    Singapore
    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
    LVLS
    UPUV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    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 years8
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 30
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 30
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 80
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 120
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients who enroll in the optional long-term follow up sub-study will
    be followed for up to 5 years post-transplantation.
    Os pacientes que se inscreverem no estudo secundário de seguimento a longo prazo opcional serão seguidos por até 5 anos após o transplante.
    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 Decision2019-01-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-29
    P. End of Trial
    P.End of Trial StatusCompleted
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