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    Summary
    EudraCT Number:2019-001453-10
    Sponsor's Protocol Code Number:BA41510
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2019-08-09
    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 number2019-001453-10
    A.3Full title of the trial
    A MULTICENTER, LOW-INTERVENTIONAL STUDY DOCUMENTING THE EFFICACY, HEALTH-RELATED QUALITY OF LIFE, AND SAFETY OF STANDARD-OF-CARE TREATMENT WITH ECULIZUMAB OR TREATMENT WITH RAVULIZUMAB IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
    ESTUDIO MULTICÉNTRICO DE BAJO NIVEL DE INTERVENCIÓN PARA DOCUMENTAR LA EFICACIA, LA CALIDAD DE VIDA RELACIONADA CON LA SALUD Y LA SEGURIDAD DEL TRATAMIENTO DE REFERENCIA CON ECULIZUMAB O EL TRATAMIENTO CON RAVULIZUMAB EN PACIENTES CON HEMOGLOBINURIA PAROXÍSTICA NOCTURNA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Low-Interventional Study Documenting the Efficacy, Health-Related Quality of Life, and Safety of Standard-Of-Care Treatment with Eculizumab or Treatment with Ravulizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria
    Un estudio de baja intervención que documenta la eficacia, la calidad de vida relacionada con la salud y la seguridad del tratamiento se referencia con eculizumab o el tratamiento con ravulizumab en pacientes con hemoglobinuria nocturna paroxística
    A.4.1Sponsor's protocol code numberBA41510
    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 SponsorRoche Farma S. A. U. que realiza el ensayo en España y que actua como representante F.Hoffmann-La Roche Ltd
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF. Hoffman-La Roche Ltd.
    B.4.2CountrySwitzerland
    B.4.1Name of organisation providing supportChugai Pharmaceutical Co. Ltd
    B.4.2CountryJapan
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF.Hoffmann-La Roche Ltd.
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4047
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number34913253700
    B.5.5Fax number34913248196
    B.5.6E-mailspain.start_up_unit@roche.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Soliris 300
    D.2.1.1.2Name of the Marketing Authorisation holderAlexion Europe SAS
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameECULIZUMAB
    D.3.4Pharmaceutical form Concentrate for solution 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 INNECULIZUMAB
    D.3.9.1CAS number 219685-50-4
    D.3.9.4EV Substance CodeSUB25187
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 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 Yes
    D.2.1.1.1Trade name ULTOMIRIS
    D.2.1.1.2Name of the Marketing Authorisation holderAlexion Europe SAS
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameUltomiris
    D.3.4Pharmaceutical form Concentrate for solution 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 INNRAVULIZUMAB
    D.3.9.3Other descriptive nameUltomiris
    D.3.9.4EV Substance CodeSUB192773
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Paroxysmal nocturnal hemoglobinuria (PNH) that is treated with either eculizumab or ravulizumab as per local label
    Hemoglobinuria paroxística nocturna (HPN) que se trata con eculizumab o ravulizumab según la etiqueta local
    E.1.1.1Medical condition in easily understood language
    PNH is a rare, acquired life-threatening disease, characterized by presence of impaired red blood cells that are easily destroyed, leading to hemoglobin in the urine and anemia as main manifestations
    HPN es enfermedad rara, adqui q pone en peligro la vida, por la presencia de glóbu rojos deteriorados q se destruyen fácil, lo q lleva a la hemoglobina en orina y anemia como manifestaciones ppales
    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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10055629
    E.1.2Term Paroxysmal nocturnal hemoglobinuria
    E.1.2System Organ Class 100000004857
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To document the efficacy of standard of care (SOC) treatment with eculizumab on the basis of lactate dehydrogenase (LDH) levels over time under routine clinical practice
    Documentar la eficacia del tratamiento estándar de atención (SOC) con eculizumab sobre la base de los niveles de lactato deshidrogenasa (LDH) a lo largo del tiempo en la práctica clínica habitual
    E.2.2Secondary objectives of the trial
    - To document the efficacy of ravulizumab on the basis of LDH levels over time under routine clinical practice
    - To document the efficacy (inclusive of health-related quality of life [HRQoL]), safety, pharmacokinetics, pharmacodynamics (PD), treatment satisfaction, and health status of SOC treatment with eculizumab or treatment with ravulizumab on the basis ofoccurrence of breakthrough hemolysis, number of blood transfusions, units of packed red blood cells transfused, hemoglobin and haptoglobin levels over time, serum concentration and HRQoL assessed by Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) questionnaire, Euro Quality of life 5-Dimension Questionnaire (5-level version; EQ-5D-5L) index-based and visual analog scale scores
    - To evaluate the safety on basis of incidence and severity of adverse events
    - To evaluate PD biomarkers
    -Documentar la concentración de LDH a lo largo del tiempo en la práctica clínica habitual con ravulizumab
    -Para documentar la eficacia (incluida la calidad de vida relacionada con la salud [CVRS]), la seguridad, la farmacocinética, la farmacodinámica (PD), la satisfacción con el tratamiento y el estado de salud del tratamiento con SOC con eculizumab o el tratamiento con ravulizumab sobre la base de la incidencia de hemólisis penetrante, número de transfusiones de sangre, unidades de glóbulos rojos empaquetados transfundidos, niveles de hemoglobina y hepatoglobina a lo largo del tiempo, concentración sérica y CVRS evaluados por el Cuestionario de Satisfacción con el Tratamiento para el Medicamento-9 (TSQM-9), Cuestionario sobre la calidad de vida del euro 5 (5 -nivel de versión; EQ-5D-5L) puntajes de escala analógica visual y basada en índices
    -Evaluar la seguridad sobre la incidencia e intensidad de los acontecimientos adversos
    -Recoger biomarcadores farmacodinámicos.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Age ≥ 12 years
    - Willingness and ability to comply with all the study visits and procedures
    - Documented diagnosis of PNH, confirmed by high sensitivity flow cytometry evaluation of RBCs with granulocyte or monocyte clone size of ≥ 10%, within 6 months prior to study enrollment
    - Documented treatment with eculizumab or ravulizumab with dose and frequency according to local label for PNH
    * Patients treated with eculizumab must have received a stable eculizumab dose for at least 4 months prior to study enrollment
    - LDH level ≤ 2 × upper limit of normal (ULN) at screening
    - Vaccination against Neisseria meningitidis < 3 years prior to study enrollment
    - For patients < 18 years: vaccination against Haemophilius infuenzae type B and Streptococcus pneumonia with strict adherence to national vaccination recommendations (e.g., Advisory Committee on Immunization Practices guidelines) for each group
    - For patients receiving other therapies (e.g., immunosuppressants, corticosteroids, iron supplements, anticoagulants): stable dose for ≥ 28 days prior to screening
    - For women of childbearing potential: agreement to follow contraception requirements as described in the eculizumab or ravulizumab summary of product characteristics or local label information
    - Negative for hepatitis B surface antigen; hepatitis B core antibody
    * Patients who are seropositive for hepatitis B virus (HBV) but adequately treated without detectable HBV DNA are eligible
    Note: patients who have been vaccinated against HBV are eligible.
    - Negative for hepatitis C virus antibody
    * Patients who are seropositive for HCV but adequately treated without detectable HCV RNA are eligible
    - Patients with known HIV infection are eligible, provided their CD4 counts are > 200 cells/µL and they meet all other criteria
    - Adequate hepatic and renal function, at screening
    •Edad mínima de 12 años
    •Disposición y capacidad para cumplir todas las visitas y procedimientos del estudio.
    •Diagnóstico documentado de HPN, confirmado mediante una evaluación de eritrocitos por citometría de flujo de alta sensibilidad con un tamaño del clon de granulocitos o monocitos ≥ 10%, en los 6 meses previos a la inclusión en el estudio
    •Tratamiento documentado con eculizumab o ravulizumab en una dosis y frecuencia conformes a la ficha técnica local en caso de HPN.
    -Los pacientes tratados con eculizumab deberán haber recibido una dosis estable durante al menos 4 meses antes de su inclusión en el estudio.
    •Concentración de LDH ≤ 2 veces el LSN en la fase de selección
    •Vacunación contra Neisseria meningitidis menos de 3 años antes de la inclusión en el estudio
    •Pacientes menores de 18 años: vacunación contra Haemophilius infuenzae de tipo B y Streptococcus pneumoniae con estricto cumplimiento de las recomendaciones nacionales de vacunación (p. ej., directrices del ACIP) en cada grupo
    •Pacientes que reciban otros tratamientos (p. ej., inmunodepresores, corticosteroides, suplementos de hierro o anticoagulantes): dosis estable durante un mínimo de 28 días antes de la selección.
    •Mujeres en edad fértil: compromiso de seguir los requisitos de anticoncepción descritos en el resumen de las características del producto o en la ficha técnica local de eculizumab o ravulizumab
    •Negatividad para el antígeno de superficie del virus de la hepatitis B (HBsAg).Podrán participar pacientes seropositivos para el virus de la hepatitis B (VHB) pero debidamente tratados, sin ADN del VHB detectable (sensibilidad del análisis ≤ 10 UI/ml).
    Nota: Podrán participar pacientes que hayan sido vacunados contra el VHB.
    •Negatividad para anticuerpos contra el virus de la hepatitis C (VHC).
    Podrán participar pacientes seropositivos para el VHC pero debidamente tratados, sin ARN del VHC detectable
    •Podrán participar pacientes con infección conocida por el VIH siempre que el recuento de CD4 sea superior a 200 células/µl y cumplan todos los demás criterios.
    •Función hepática adecuada en la fase de selección
    E.4Principal exclusion criteria
    - Major adverse vascular event within 6 months prior to study enrollment
    - Platelet count < 30000/mm3 at screening
    - ANC < 500/µL at screening
    - Body weight < 40 kg at screening
    - History of bone marrow transplantation
    - History of Neisseria meningitides infection within prior 6 months of enrollment
    - Known or suspected immune deficiency
    - Active systemic bacterial, viral, or fungal infection within 14 days prior to study enrollment
    - No major episode of infection requiring hospitalization or treatment with IV antibiotics within 28 days prior to screening or oral antibiotics within 2 weeks prior to screening and up to study enrollment
    - Presence of fever within 7 days prior to study enrollment
    - Immunized with a live attenuated vaccine within 1 month prior to study enrollment
    - History of malignancy, including myelodysplastic syndrome, within 5 years of screening with the following exceptions:
    * Patients with any malignancy appropriately treated with curative intent and the malignancy has been in remission without treatment for > 5 years prior to study enrollment are eligible
    * Patients with curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix at any time prior to study enrollment are eligible
    * Patients with low-grade, early-stage prostate cancer with no requirement for therapy at any time prior to study enrollment are eligible
    - History of ongoing major cardiac, pulmonary, renal, endocrine, or hepatic disease that, in the opinion of the investigator or Sponsor, precludes the patient’s participation in an investigational clinical trial
    - Unstable medical conditions (e.g., myocardial ischemia, active gastrointestinal bleed, severe congestive heart failure, anticipated need for major surgery within 12 months of study enrollment, coexisting chronic anemia unrelated to PNH) that would make the patient unlikely to tolerate the requirements of the interventional study on crovalimab
    - History of hypersensitivity, allergic, or anaphylactic reactions to any ingredient contained in eculizumab or ravulizumab or crovalimab, including hypersensitivity to human, humanized, or murine monoclonal antibodies or known hypersensitivity to any constituent of the product
    - Pregnancy or breastfeeding, or intention of becoming pregnant during the study
    - Participation in another interventional treatment study or use of any experimental therapy within 30 days or within 5 half-lives of that investigational product prior to study enrollment, with the following exception:
    Patients enrolled in an eculizumab or ravulizumab interventional study are eligible provided they fulfill eligibility (e.g., are willing and able to comply with the study assessments)
    - Known medical or psychological condition or risk factor that, in the opinion of the investigator, might interfere with the patient’s participation in this study, pose any additional risk for the patient, or confound the assessment of the patient or outcome of this study and the interventional study of crovalimab
    - Known or suspected hereditary complement deficiency
    - Treatment with azathioprine or erythrocyte-stimulating agents within 14 days prior to study enrollment
    - Splenectomy < 6 months prior to study enrollment
    - Diagnosis of auto-immune connective tissue diseases
    - Any evidence of active inflammatory conditions
    •Episodio vascular adverso importante en los 6 meses previos a la inclusión en el estudio.
    •Recuento de plaquetas < 30.000/mm3 en la fase de selección.
    •RAN < 500/µl en la fase de selección.
    •Peso corporal < 40 kg en la fase de selección.
    •Antecedentes de trasplante de médula ósea.
    •Antecedentes de infección por Neisseria meningitidis en los 6 meses
    •Inmunodeficiencia conocida o sospechada previos a la inclusión.
    •Infección bacteriana, vírica o micótica sistémica activa en los 14 días previos a la inclusión en el estudio.
    •Episodio importante de infección con necesidad de hospitalización o tratamiento con antibióticos IV en los 28 días previos a la selección o con antibióticos orales en las 2 semanas previas a la selección y hasta la inclusión en el estudio.
    •Presencia de fiebre en los 7 días previos a la inclusión en el estudio.
    •Vacunación con una vacuna de microorganismos vivos atenuados en el mes previo a la inclusión en el estudio.
    •Antecedentes de neoplasias malignas, incluido síndrome mielodisplásico, en los 5 años previos a la selección con las siguientes excepciones:
    Podrán participar pacientes con cualquier neoplasia maligna debidamente tratada con intención curativa y que hayan permanecido en remisión sin tratamiento durante más de 5 años antes de la inclusión en el estudio
    Podrán participar pacientes con antecedentes de carcinoma basocelular o espinocelular o melanoma de piel o de carcinoma in situ de cuello uterino tratado con intención curativa en cualquier momento antes de la inclusión en el estudio.
    Podrán participar pacientes con cáncer de próstata de bajo grado en estadio inicial que no hayan necesitado tratamiento en ningún momento antes de la inclusión en el estudio.
    •Antecedentes de enfermedad cardíaca, pulmonar, renal, endocrina o hepática importante en curso que, en opinión del investigador o promotor, impida la participación del paciente en un ensayo clínico de investigación
    •Enfermedades inestables (p. ej., isquemia miocárdica, hemorragia digestiva activa, insuficiencia cardíaca congestiva grave, necesidad prevista de cirugía mayor en los 12 meses siguientes a la inclusión en el estudio o anemia crónica coexistente no relacionada con la HPN) que hagan improbable que el paciente tolere los requisitos del estudio intervencionista de crovalimab.
    •Antecedentes de reacciones de hipersensibilidad, alérgicas o anafilácticas a cualquiera de los componentes contenidos en eculizumab, ravulizumab o crovalimab, incluida la hipersensibilidad a anticuerpos monoclonales humanos, humanizados o murinos o la hipersensibilidad conocida a cualquiera de los componentes del producto.
    •Embarazo o lactancia materna, o intención de quedarse embarazada
    durante el estudio.
    •Participación en otro estudio intervencionista o uso de cualquier tratamiento experimental en los 30 días previos a la inclusión en el estudio o en el período equivalente a 5 semividas de ese producto experimental con la siguiente excepción:
    Podrán participar pacientes incluidos en un estudio intervencionista con eculizumab o ravulizumab siempre que cumplan los criterios de elegibilidad (p. ej., estén dispuestos y sean capaces de cumplir las evaluaciones del estudio
    •Trastorno o factor de riesgo médico o psicológico conocido que, en opinión del investigador, pueda interferir en la participación del paciente en este estudio, suponer un riesgo adicional para el paciente o confundir la evaluación del paciente o los resultados de este estudio y del estudio intervencionista de crovalimab.
    •Sospecha o certeza de deficiencia hereditaria del complemento.
    •Tratamiento con azatioprina o fármacos estimuladores de los eritrocitos en los 14 días previos a la inclusión en el estudio.
    •Esplenectomía en los 6 meses previos a la inclusión en el estudio.
    •Diagnóstico de enfermedades autoinmunitarias del tejido conjuntivo
    •Cualquier indicio de procesos inflamatorios activos
    E.5 End points
    E.5.1Primary end point(s)
    1. Document LDH levels over time under routine clinical practice with eculizumab treatment
    •Documentar la concentración de LDH a lo largo del tiempo en la práctica clínica habitual con eculizumab.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Day 1, 29, 57, 85, 113, 141,169, 197, 225, 253, 281 (Q4W [every 4 weeks]) beyond and at treatment discontinuation (TD)
    Día 1, 29, 57, 85, 113, 141,169, 197, 225, 253, 281 (Q4W [cada 4 semanas]) más allá y al interrumpir el tratamiento (TD)
    E.5.2Secondary end point(s)
    1. Document LDH levels over time under routine clinical practice with ravulizumab
    2. Document occurrence of breakthrough hemolysis (BTH)
    3. Document the number of units of packed red blood cells transfused
    4. Document the number of blood transfusions
    5. Document hemoglobin and haptoglobin levels over time
    6. Document serum concentration of eculizumab or ravulizumab
    7. Health -related quality of life as assessed by the Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue, selected scales of the European Organisation for Research and Treatment of
    Cancer (EORTC) Quality of Life-Questionnaire-Core-30, and selected PNH-relevant symptoms from the EORTC Item Library
    8. Health status as assessed by the Euro Quality of life 5-Dimension Questionnaire (5-level version; EQ-5D-5L) index-based and visual analog scale scores
    9. Information on treatment satisfaction as assessed by the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) questionnaire in adult patients with PNH
    10. Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0
    11. Pharmacodynamic biomarkers
    1. Documentar los niveles de LDH a lo largo del tiempo en la práctica clínica habitual con ravulizumab
    2. Documentación de ocurrencia de hemólisis de avance (BTH)
    3. Documentar el número de unidades de glóbulos rojos empaquetados transfundidos
    4. Documentar el número de transfusiones de sangre.
    5. Documentar los niveles de hemoglobina y haptoglobina a lo largo del tiempo.
    6. Documente la concentración sérica de eculizumab o ravulizumab.
    7. Calidad de vida relacionada con la salud según lo evaluado por la Evaluación funcional de la terapia de enfermedades crónicas (FACIT) -Fatiga, escalas seleccionadas de la Organización Europea para la Investigación y el Tratamiento de
    Cáncer (EORTC), Quality of Life-Questionnaire-Core-30, y síntomas seleccionados relevantes para la HPN de la Biblioteca de artículos de la EORTC
    8. Estado de salud según lo evaluado por el Cuestionario de 5 dimensiones Euro Calidad de vida (versión de 5 niveles; EQ-5D-5L) basado en índices y en escalas analógicas visuales
    9. Información sobre la satisfacción con el tratamiento según lo evaluado por el Cuestionario de satisfacción con el tratamiento para el medicamento 9 (TSQM-9) en pacientes adultos con HPN
    10. Incidencia y gravedad de los eventos adversos, y la gravedad se determina de acuerdo con los Criterios de Terminología Comunes del National Cancer Institute para Eventos Adversos v5.0
    11. Biomarcadores farmacodinámicos.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Day 1,57,113,169,225,281 (Q8W) beyond and at TD
    2-4. Eculizumab cohort (EC): Day 1, 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 183, 197, 211, 225, 239, 253, 267, 281 (Q2W) beyond; Ravulizumab cohort (RC): Day 1, 57, 113, 169, 225, 281 (Q8W) beyond and at TD
    5-6. EC: Day 1, 29, 57, 85, 113, 141,169, 197, 225, 253, 281 (Q4W) beyond and at TD; RC: Day 1, 57, 113, 169, 225, 281 (Q8W) beyond and at TD
    7-8. EC: Day 1,57,113,169,225,281 (Q8W) beyond and at TD; RC: Day 1,57,113,169,225,281 (Q8W) beyond and at TD
    9. EC and RC: Day 113
    10. Until the study completion
    11. For PNH clone size and C3d only: EC: Day 1, 71 and at TD; RC: Day 1, 57 and at TD Others: for EC day 1, 29, 57, 71, 85, 113, 141,169, 197, 225, 253, (Q4W) beyond, for RC: Day 1, 57, 113, 169, 225 (Q8W) beyond
    1. Día 1,57,113,169,225,281 (Q8W) más allá y en el TD
    2-4. Cohorte de Eculizumab (EC): Día 1, 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 183, 197, 211, 225, 239, 253, 267, 281 (Q2W ) más allá de Cohorte de Ravu(RC): Día 1, 57, 113, 169, 225, 281 (Q8W) más allá y en el TD,5-6. EC: Día 1, 29, 57, 85, 113, 141,169, 197, 225, 253, 281 (Q4W) más allá y en el TD; RC: Día 1, 57, 113, 169, 225, 281 (Q8W) más allá y en el TD 7-8. EC: Día 1,57,113,169,225,281 (Q8W) más allá y en TD; RC: Día 1,57,113,169,225,281 (Q8W) o mas y en el TD
    9. EC y RC: día 113,10. Hasta fin del estudio.
    11. Para el tamaño de clon de PNH y C3d : EC: Día 1, 71 y en TD; RC: Día 1, 57 y en TD : para EC día 1, 29, 57, 71, 85, 113, 141,169, 197, 225, 253, (Q4W) más allá, para RC: Día 1, 57, 113, 169 , 225 (Q8W) más allá
    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 No
    E.6.5Efficacy No
    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 Yes
    E.6.13.1Other scope of the trial description
    Document the efficacy of the standard of care treatment with eculizumab and ravulizumab on the basis of lactate dehydrogenase (LDH) levels over time under routine clinical practice
    Documentar la eficacia del tratamiento estándar con eculizumab y ravulizumab sobre la base de los niveles de lactato deshidrogenasa (UVUP) a lo largo del tiempo en la práctica clínica habitual
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    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
    Argentina
    Brazil
    Canada
    Colombia
    Czech Republic
    France
    Germany
    Greece
    Hungary
    Israel
    Italy
    Japan
    Korea, Republic of
    Netherlands
    Poland
    Romania
    Spain
    Sweden
    Taiwan
    Turkey
    United Kingdom
    United States
    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
    LPLV. This is expected to occur when the last eculizumab-treated patient is either followed for at least 30 weeks, and all patients (eculizumab- and ravulizumab-treated) have either rolled over to the interventional Phase III study or discontinued from the low-interventional study
    El final del estudio se define como la fecha de la última visita del último paciente (UVUP) Se espera que esto ocurra cuando el último paciente tratado con eculizumab haya sido objeto de seguimiento durante al menos 30 semanas y todos los pacientes (tratados con eculizumab y ravulizumab) hayan pasado al estudio intervencionista de fase III o se hayan retirado del estudio de bajo nivel de intervención
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months18
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months18
    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: 12
    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: 12
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 134
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 54
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 76
    F.4.2.2In the whole clinical trial 200
    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)
    After study, patients will continue their SOC-treatment. In addition they will be invited to participate in study BO40574.
    Después del estudio, los pacientes continuarán su tratamiento con SOC. Además serán invitados a participar en el estudio BO40574
    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 Decision2019-09-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-09-05
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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