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    Summary
    EudraCT Number:2020-001160-28
    Sponsor's Protocol Code Number:MedOPP376
    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:2020-04-13
    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 number2020-001160-28
    A.3Full title of the trial
    A Randomized, Controlled, Open-Label, Phase II Trial to Evaluate the Efficacy and Safety of Tocilizumab Combined with Pembrolizumab (MK-3475) in Patients with Coronavirus Disease 2019 (COVID-19)-Pneumonia Who Are Unresponsive to Standard Care
    Estudio de fase II, aleatorizado, abierto y controlado para evaluar la
    eficacia y seguridad de la combinación de tocilizumab con pembrolizumab (MK-3475) en pacientes con neumonía causada por coronavirus 2019 (COVID-19) que no responden al tratamiento estándar.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Tocilizumab plus Pembrolizumab in COVID-19
    Tocilizumab más pembrolizumab en la COVID-19
    A.3.2Name or abbreviated title of the trial where available
    Tocilizumab plus Pembrolizumab in COVID-19 (COPERNICO Study)
    Tocilizumab más Pembrolizumab en la COVID-19 (Estudio COPÉRNICO)
    A.4.1Sponsor's protocol code numberMedOPP376
    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 SponsorMedica Scientia Innovation Research S.L. (MEDSIR)
    B.1.3.4CountrySpain
    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 supportMedica Scientia Innovation Research S.L. (MEDSIR)
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedica Scientia Innovation Research S.L. (MEDSIR)
    B.5.2Functional name of contact pointClinical Trial Unit
    B.5.3 Address:
    B.5.3.1Street AddressTorre Glòries. Avenida Diagonal, 211, planta 27
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08018
    B.5.3.4CountrySpain
    B.5.4Telephone number34932214135
    B.5.6E-mailregulatory@medsir.org
    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 KEYTRUDA
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.4Pharmaceutical form 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 INNPembrolizumab
    D.3.9.2Current sponsor codeMK3475
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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) Yes
    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 RoActemra
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameTocilizumab
    D.3.4Pharmaceutical form 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 INNTOCILIZUMAB
    D.3.9.1CAS number 375823-41-9
    D.3.9.3Other descriptive nameTOCILIZUMAB
    D.3.9.4EV Substance CodeSUB20313
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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) Yes
    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
    Coronavirus Disease 2019 (COVID-19)-Pneumonia
    Infección por COVID-19 - neumonía
    E.1.1.1Medical condition in easily understood language
    Coronavirus Disease 2019 (COVID-19)-Pneumonia
    Infección por COVID-19 - neumonía
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10051905
    E.1.2Term Coronavirus infection
    E.1.2System Organ Class 100000004862
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the efficacy –as determined by the proportion of patients with normalization of SpO2 ≥96%– of continued standard care together with tocilizumab plus pembrolizumab (MK-3475) in patients with COVID-19 pneumonia who are nonresponsive to frontline therapy within 48 hours from treatment initiation.
    Evaluar la eficacia (determinada por la proporción de pacientes con normalización de la SpO2 ≥96 %) de la continuación del tratamiento de referencia junto con la administración de tocilizumab más pembrolizumab (MK-3475) en pacientes con neumonía asociada a la COVID-19 sin respuesta al tratamiento de referencia de primera línea en las 48 horas posteriores al inicio del tratamiento.
    E.2.2Secondary objectives of the trial
    To assess the efficacy –as determined by:
    the proportion of patients with normalization of fever– of study drugs in this population.
    • the proportion of discharged patients– of study drugs in this population.
    • the duration of hospitalization– of study drugs in this population.
    • the Sequential Organ Failure Assessment (SOFA)– of study drugs in this population.
    • the mortality rate– of study drugs in this population.
    • the remission of respiratory symptoms– of study drugs in this population in terms of:
    -Time to invasive mechanical ventilation;
    -Time to independence from oxygen therapy.
    • the radiological response– of study drugs in this population.
    • the severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 negativization– of study drugs in this population.
    •the change in laboratory parameters– of study drugs in this population.
    •To evaluate the safety and tolerability of study drugs in this population.
    Evaluar la eficacia de los fármacos del estudio en esta población - determinada por:
    •por la proporción de pacientes con normalización de la fiebre
    •por la proporción de pacientes a los que se les ha dado el alta hospitalaria
    •por la duración de la hospitalización.
    •por la evaluación de la insuficiencia orgánica secuencial [SOFA])
    •(determinada por la tasa de mortalidad) de los fármacos del estudio en esta población
    •determinada por la remisión de los síntomas respiratorios .
    -Tiempo transcurrido hasta la aplicación de ventilación mecánica invasiva.
    -Tiempo transcurrido hasta alcanzar la independencia de la administración de oxígeno.
    •determinada por la respuesta radiográfica
    •determinada por la negativización del coronavirus 2 del síndrome respiratorio agudo grave [SARS-CoV-2] .
    •determinada por el cambio de los parámetros analíticos.
    •Evaluar la seguridad y la tolerabilidad
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Informed consent form (ICF) prior to participation in any study-related activities.
    2. Male or nonpregnant female patients ≥ 18 years and ≤ 80 years at the time of ICF.
    3. Laboratory confirmed COVID-19 infection defined with a positive RT-PCR from any specimen and/or detection of SARS-CoV-2 immunoglobulin (Ig)M/IgG antibodies.
    4. Diagnostic confirmation of pneumonia by either chest X-ray or thoracic computed tomography (CT) scan (preferable).
    5. Patient with acute respiratory syndrome related to COVID-19 under treatment as per hospital protocol during at least 48 hours.
    6. Patients with SOFA score ≤ 3 at the time of ICF.
    7. Patients hospitalized with fever defined as temperature ≥ 37,5 °C armpit.
    8. Patients with total lymphocyte count ≤0,8 x106/mL.
    9. Patients who are showing SpO2 ≤ 92% on room air and/or patient who are showing SpO2 ≤ 94% on room air and meet at least one of the following parameters:
    • No objective clinical improvement at physician’s discretion after 48 hours of front-line standard care for COVID-19;
    • Decrease in lymphocyte count (any decrease within 48 hours);
    • Increase in ferritin levels (any increase within 48 hours);
    • Increase in IL-6 levels (any increase within 48 hours);
    • Increase in D-dimer levels (any increase within 48 hours);
    • Increase in CRP levels (any increase within 48 hours);
    • Increase in LDH levels (any increase within 48 hours);
    • Increase in ESR levels (any increase within 48 hours).
    10. Life expectancy greater than 10 days.
    11. Willing to take study medication and to comply with all study procedures.
    12. In women of childbearing potential, negative pregnancy test and commitment to use contraceptive method throughout the study.
    1. Formulario de consentimiento informado (FCI) previo a la participación en cualquier actividad relacionada con el estudio.
    2. Pacientes varones o mujeres no embarazadas ≥18 años y ≤80 años en el momento de la firma del FCI.
    3. Infección por COVID-19 confirmada analíticamente definida por un resultado positivo de RT-PCR en cualquier muestra y/o la detección de anticuerpos de inmunoglobulinas (Ig)M/IgG contra el SARS-CoV-2.
    4. Confirmación del diagnóstico de neumonía mediante radiografía de tórax o tomografía axial computarizada (TAC) torácica (preferible).
    5. Paciente con síndrome respiratorio agudo relacionado con la COVID-19 en tratamiento según el protocolo hospitalario durante al menos 48 horas.
    6. Pacientes con puntuación de SOFA ≤3 en el momento de la firma del FCI.
    7. Pacientes hospitalizados con fiebre definida como temperatura axilar ≥37,5 °C.
    8. Pacientes con cifra total de linfocitos ≤0,8 x106/ml.
    9. Pacientes que presentan una SpO2 ≤92 % en el aire ambiente o pacientes que presentan una SpO2 ≤94 % en el aire ambiente y reúnen al menos uno de los siguientes parámetros:
    • Ausencia de mejoría clínica objetiva según el criterio del médico después de 48 horas con el tratamiento de referencia de primera línea para la COVID-19.
    • Disminución de la cifra de linfocitos (cualquier disminución en 48 horas).
    • Aumento de los niveles de ferritina (cualquier aumento en 48 horas).
    • Aumento de los niveles de IL-6 (cualquier aumento en 48 horas).
    • Aumento de los niveles de dímero D (cualquier aumento en 48 horas).
    • Aumento de los niveles de CRP (cualquier aumento en 48 horas).
    • Aumento de los niveles de LDH (cualquier aumento en 48 horas).
    • Aumento de los niveles de ESR (cualquier aumento en 48 horas).
    10. Esperanza de vida superior a 10 días.
    11. Estar dispuesto/a a tomar la medicación del estudio y a cumplir con todos los procedimientos del estudio.
    12. En las mujeres con capacidad para quedarse embarazadas, una prueba de embarazo con resultado negativo y el compromiso de usar algún método anticonceptivo durante todo el estudio.
    E.4Principal exclusion criteria
    1. Participation in any other clinical trial of an experimental treatment for COVID-19.
    2. Concurrent treatment with other agents with actual or possible direct acting antiviral activity against SARS-CoV-2 is prohibited < 24 hours prior to study drug dosing, except the commonly used antiviral drugs and/or chloroquine.
    3. Requiring endotracheal intubation, mechanical ventilation, and extracorporeal membrane oxygenation (ECMO) at screening.
    4. Patients being treated with immunomodulators or anti-rejection drugs.
    5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 x upper limit of normal (ULN).
    6. Creatinine clearance < 50 mL/min.
    7. Chronic Obstructive Pulmonary Disease (COPD) or end-stage lung disease that require home oxygen therapy.
    8. Known hypersensitivity to recombinant proteins, or any excipient contained in the drug formulation of study pembrolizumab and tocilizumab.
    9. Treatment with high doses of systemic corticosteroids within 72 hours prior obtaining consent except for inhaled steroids and prior corticosteroid therapy at dose lower than or equal to 10 mg/day methylprednisolone equivalent.
    10. Bowel diverticulitis or perforation.
    11. Diagnosis of immunodeficiency receiving immunosuppressive therapy within seven days prior to study treatment initiation. Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).
    12. Current known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients with past HBV infection or resolved HBV infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive hepatitis B core antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible. Patients positive for HCV antibody are eligible only if PCR test is negative for HCV ribonucleic acid (RNA).
    13. Vaccination with any live virus vaccine within 28 days prior to study treatment initiation.
    Note: Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox/zoster, yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live-attenuated vaccines and are not allowed.
    14. History of prior allogeneic bone marrow, stem-cell, or solid organ transplantation.
    15. Patients have any other concurrent severe medical condition that would, in the Investigator’s judgment contraindicate patient participation in the clinical study.
    16. Pregnant women, lactating women and planned pregnant women.
    1. Participación en cualquier otro ensayo clínico sobre un tratamiento experimental para la COVID-19.
    2. El tratamiento concomitante con otros fármacos con actividad antivírica de acción directa real o posible contra el SARS-CoV-2 no está permitido <24 horas antes de la administración del fármaco del estudio, excepto los antivirales de uso habitual o la cloroquina.
    3. Necesidad de intubación endotraqueal, ventilación mecánica y oxigenación por membrana extracorpórea (ECMO) en la selección.
    4. Pacientes en tratamiento con inmunomoduladores o antirrechazo.
    5. Alanina-aminotransferasa (ALT) o aspartato-aminotransferasa (AST) >5 x límite superior de la normalidad (LSN).
    6. Aclaramiento de creatinina <50 ml/min.
    7. Enfermedad pulmonar obstructiva crónica (EPOC) o neumopatía terminal con necesidad de oxigenoterapia domiciliaria.
    8. Hipersensibilidad conocida a proteínas recombinantes o a cualquier excipiente contenido en la formulación de los fármacos del estudio, pembrolizumab y tocilizumab.
    9. Tratamiento con dosis elevadas de corticoesteroides sistémicos en las 72 horas previas a la obtención del consentimiento, a excepción de los corticoesteroides inhalados y el tratamiento previo con corticoesteroides a dosis inferiores o iguales a 10 mg/día de un equivalente a la metilprednisolona.
    10. Diverticulitis o perforación intestinal.
    11. Diagnóstico de inmunodeficiencia en tratamiento con inmunodepresores en los siete días previos al inicio del tratamiento del estudio. Enfermedad autoinmunitaria activa que ha requerido tratamiento sistémico en los últimos 2 años (es decir, uso de fármacos modificadores de la enfermedad, corticoesteroides o inmunodepresores).
    12. Infección conocida actual por el virus de la inmunodeficiencia humana (VIH), el virus de la hepatitis B (VHB) o el virus de la hepatitis C (VHC). Se consideran aptos los pacientes con infección por el VHB pasada o resuelta (definida como resultado negativo en la prueba del antígeno de superficie de la hepatitis B [HBsAg] y resultado positivo en la prueba del anticuerpo central del virus de la hepatitis B [HBcAb], acompañadas por un resultado negativo en la prueba del ADN del VHB). Los pacientes positivos para el anticuerpo del VHC se consideran aptos solo si la prueba de la PCR resulta negativa para el ácido ribonucleico del VHC (ARN).
    13. Vacunación con una vacuna elaborada con virus vivos en los 28 días previos al inicio del tratamiento del estudio.
    Nota: ejemplos de vacunas elaboradas con microbios vivos son, entre otras, el sarampión, las paperas, la rubéola, la varicela/zóster, la fiebre amarilla, la rabia, el bacilo de Calmette y Guérin (BCG) y la vacuna antitifoidea. En general, las vacunas inyectables contra la gripe estacional son vacunas elaboradas con virus muertos y están permitidas. Sin embargo, las vacunas intranasales de la gripe (por ejemplo, FluMist®) son vacunas atenuadas y no están permitidas.
    14. Antecedentes de alotrasplante previo de médula ósea, células madre o trasplante de vísceras macizas.
    15. Pacientes que presentan cualquier otra enfermedad grave concomitante que, a criterio del investigador, podría contraindicar la participación del paciente en el estudio clínico.
    16. Mujeres embarazadas, en periodo de lactancia o que planean quedarse embarazadas.
    E.5 End points
    E.5.1Primary end point(s)
    Percentage of patients with normalization of SpO2 ≥96% through day 14 after study treatment initiation
    Porcentaje de pacientes con normalización de la SpO2 ≥96 % hasta el día 14 después del inicio del tratamiento del estudio.
    E.5.1.1Timepoint(s) of evaluation of this end point
    through day 14 after study treatment initiation.
    hasta el día 14 después del inicio del tratamiento del estudio
    E.5.2Secondary end point(s)
    1.Percentage of patients with temperature <37,5 °C armpit through hospital discharge.
    2.Percentage of patients discharged from the hospital through end of study (EoS) (90 ± 14 days after study entry).
    3.Number of days of hospitalization from baseline until EoS (90 ± 14 days after study entry ).
    4.Change from baseline in SOFA score evaluated at day 1, 3, 5, 7, 14, 21, 28, and thereafter once weekly until hospital discharge only in case of an additional dosing.
    5.Percentage of dead patients through EoS (90 ± 14 days after study entry ).
    6.Remission of respiratory symptoms through EoS (90 ± 14 days after study entry ) in terms of:
    - Number of days of intubation;
    - Date of independence from oxygen therapy.
    7.Change in radiological response from baseline to hospital discharge by using the same imaging technique.
    8.Percentage of patients with SARS-CoV-2 negative result by
    reverse transcriptase - polymerase chain reaction (RT-PCR) at
    day 14 and on day of hospital discharge.
    9.Change from baseline in both basic laboratory and inflammation parameters (see Appendix 1) at day 1, 3, 5, 7, 14, 21, 28, and thereafter once weekly until hospital discharge only in case of an additional dosing
    10.Incidence of adverse events (AEs), incidence of prespecified AEs will be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 until EoS (90 ± 14 days after study entry).
    1. Porcentaje de pacientes con temperatura axilar <37,5 °C hasta el alta hospitalaria.
    2. Porcentaje de pacientes dados de alta del hospital hasta el final del estudio (FdE) (90 ± 14 días después de la inclusión en el estudio).
    3. Número de días de hospitalización desde el inicio hasta el FdE (90 ± 14 días después de la inclusión en el estudio).
    4. Cambio desde el inicio en la escala de SOFA evaluada los días 1, 3, 5, 7, 14, 21 y 28, y una vez por semana a partir de entonces hasta el alta hospitalaria únicamente en caso de administración adicional.
    5. Porcentaje de pacientes fallecidos hasta el FdE (90 ± 14 días después de la inclusión en el estudio).
    6. Remisión de los síntomas respiratorios hasta el FdE (90 ± 14 días después de la inclusión en el estudio) en cuanto a:
    - Número de días de intubación.
    - Fecha de la independencia de la administración de oxígeno.
    7. Cambio en la respuesta radiográfica desde el inicio hasta el alta hospitalaria mediante el uso de la misma técnica de diagnóstico por imagen.
    8. Porcentaje de pacientes con resultado negativo para el SARS-CoV-2 según la reacción en cadena de la polimerasa con transcriptasa inversa (RT-PCR) el día 14 y el día del alta hospitalaria.
    9. Cambio desde el inicio en los parámetros básicos analíticos y de inflamación (véase el Apéndice 1) los días 1, 3, 5, 7, 14, 21 y 28, y una vez por semana a partir de entonces hasta el alta hospitalaria únicamente en caso de administración adicional.
    10. La incidencia de acontecimientos adversos (AA) y la incidencia de AA previamente especificados se evaluará utilizando la versión 5.0 de los criterios terminológicos comunes para acontecimientos adversos (CTCAE) hasta el FdE (90 ± 14 días después de la inclusión en el estudio).
    E.5.2.1Timepoint(s) of evaluation of this end point
    1.through hospital discharge.
    2.through end of study (EoS) (90 ± 14 days after study entry).
    3.from baseline until EoS (90 ± 14 days after study entry ).
    4.Change from baseline in SOFA score evaluated at day 1, 3, 5, 7, 14, 21, 28, and thereafter once weekly until hospital discharge only in case of an additional dosing.
    5. through EoS(90 ± 14 days after study entry).
    6. through EoS(90 ± 14 days after study entry)
    7.from baseline to hospital discharge by using the same imaging technique.
    8. day 14 and on day of hospital discharge.
    9.Change from baseline in both basic laboratory and inflammation parameters (see Appendix 1) at day 1,3,5,7,14,21,28, and thereafter once weekly until hospital discharge only in case of an additional dosing
    10. until EoS (90 ± 14 days after study entry).
    1.hasta alta hospitalaria
    2.hasta FdE (90±14 días después inclusión)
    3.desde inicio hasta FdE (90±14 días después inclusión)
    4.Cambio desde el inicio en la escala de SOFA evaluada los días 1,3,5, 7,14,21 y 28, y una vez por semana hasta el alta hospitalaria únicamente en caso de administración adicional.
    5.hasta FdE (90±14 días después inclusión).
    6.hasta FdE (90±14 días después inclusión)
    7.desde inicio hasta alta hospitalaria mediante el uso de la misma técnica de diagnóstico por imagen.
    8.día 14 y día alta hospitalaria.
    9.Cambio desde inicio en los parámetros básicos analíticos y de inflamación (véase Apéndice 1) los días 1,3,5,7,14,21 y 28, y semanalmente hasta alta hospitalaria únicamente en caso de administración adicional.
    10.hasta FdE (90±14 días después de la inclusión).
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 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) Yes
    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 concerned6
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    The EoS is defined as the last data collection point, which can be a
    clinic visit or a telephone call. EoS will occur at 90 ± 14 days after
    study entry of last patient, unless premature termination of the study
    El FdE se define como el momento de la última recogida de datos, que se puede realizar en una visita a la clínica o mediante una llamada telefónica. El FdE se producirá a los 90 ± 14 días después de la inclusión en el estudio, a menos que se produzca una finalización prematura del estudio.
    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 months
    E.8.9.1In the Member State concerned days90
    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: 8
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 16
    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.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)
    standard of care
    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 Decision2020-04-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-04-08
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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