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    Summary
    EudraCT Number:2020-002913-16
    Sponsor's Protocol Code Number:0135-0347
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2023-10-11
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2020-002913-16
    A.3Full title of the trial
    The TRISTARDS trial - ThRombolysIS Therapy for ARDS
    A Phase IIb/III operationally seamless, open-label, randomised, sequential, parallel-group adaptive study to evaluate the efficacy and safety of daily intravenous alteplase treatment given up to 5 days on top of standard of care (SOC) compared with SOC alone, in patients with acute respiratory distress syndrome (ARDS) triggered by COVID-19.
    Ensayo TRISTARDS - ThRombolysIS Therapy for ARDS (tratamiento
    trombolítico para el síndrome de dificultad respiratoria aguda)

    Ensayo en fase IIb/III, operacionalmente óptimo, abierto, aleatorizado, secuencial, de grupos paralelos, adaptativo para evaluar la eficacia y la seguridad del tratamiento con alteplasa intravenosa diaria administrado hasta 5 días además del tratamiento de referencia (SOC) en comparación con el tratamiento de referencia en monoterapia, en pacientes con síndrome de dificultad respiratoria aguda (SDRA) desencadenado por COVID-19.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The TRISTARDS trial - ThRombolysIS Therapy for ARDS A study to test whether different doses of alteplase help people with severe breathing problems because of COVID 19.
    Ensayo TRISTARDS - ThRombolysIS Therapy for ARDS (tratamiento
    trombolítico para el síndrome de dificultad respiratoria aguda)

    Ensayo para evaluar si diferentes dosis de alteplasa pueden ayudar a las personas con problemas respiratorios graves causados por la COVID-19.
    A.4.1Sponsor's protocol code number0135-0347
    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 SponsorBoehringer Ingelheim España, S.A.
    B.1.3.4CountrySpain
    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 supportBoehringer Ingelheim España, S.A.
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBoehringer Ingelheim Pharma GmbH & Co. KG
    B.5.2Functional name of contact pointCT Disclosure & Data Transparency
    B.5.3 Address:
    B.5.3.1Street AddressBinger Strasse 173
    B.5.3.2Town/ cityIngelheim am Rhein
    B.5.3.3Post code55216
    B.5.3.4CountryGermany
    B.5.4Telephone number93 404 51 00
    B.5.5Fax number93 404 55 80
    B.5.6E-mailclintriage.rdg@boehringer-ingelheim.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The 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 nameAlteplase Powder and Solvent for Solution for Injection/Infusion (TPA-05, 50 mg/vial)
    D.3.4Pharmaceutical form Powder and solvent for solution for injection/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 INNALTEPLASE
    D.3.9.1CAS number 105857-23-6
    D.3.9.4EV Substance CodeSUB05378MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 Yes
    D.3.11.13.1Other medicinal product typebiotechnologically manufactured and isolated from hamster ovarian cells
    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
    Acute respiratory distress syndrome caused by COVID-19
    Síndrome de dificultad respiratoria aguda (SDRA) desencadenado por COVID-19
    E.1.1.1Medical condition in easily understood language
    Severe breathing problems caused by COVID-19
    Problemas respiratorios graves causados por la COVID-19
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10001052
    E.1.2Term Acute respiratory distress syndrome
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy and safety of intravenous alteplase in ARDS triggered by COVID-19.
    Evaluar la eficacia y la seguridad de la alteplasa intravenosa en el SDRA desencadenado por COVID-19.
    E.2.2Secondary objectives of the trial
    Not applicable
    No aplica
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age ≥ 18 years (or above legal age, e.g. UK ≥16 years)
    2. ARDS with PaO2*/FiO2 ratio >100 and ≤300 , either on non-invasive ventilator support, OR on mechanical ventilation (<48 hours since intubation),
    • with bilateral opacities in chest X-ray or CT scan (not fully explained by effusions, lobar/lung collapse, or nodules)
    • with respiratory failure (not fully explained by cardiac failure/fluid overload)
    *or estimation of PaO2/FiO2 from pulse oximetry (SpO2/FiO2)
    3. SARS-CoV-2 positive (laboratory-confirmed RT-PCR test)
    4. Fibrinogen level ≥ upper limit of normal
    5. D-Dimer ≥ 3-fold of upper limit of normal (ULN) according to local laboratory
    6. Signed and dated written informed consent in accordance with ICH Good Clinical Practice (GCP) and local legislation prior to admission to the trial.
    1. Edad ≥18 años (o mayoría de edad legal, p. ej., ≥16 años en el Reino Unido)
    2. SDRA con cociente PaO2*/FiO2 >100 y ≤300, ya sea con respiración mecánica no invasiva O con ventilación mecánica (<48 horas desde la intubación),
    - con opacidades bilaterales en radiografía de tórax o TC (no explicadas por completo por derrames, colapso lobular o pulmonar o nódulos)
    - con insuficiencia respiratoria (no explicada por completo por insuficiencia cardíaca/sobrecarga de líquidos)
    *o estimación de la PaO2/FiO2 a partir de la pulsioximetría (SpO2/FiO2)
    3. SARS-CoV-2 positivo (prueba RT-PCR confirmada por laboratorio)
    4. Concentración de fibrinógeno ≥ límite superior de la normalidad
    5. Dímero D ≥ 3 veces el límite superior de la normalidad (LSN) según el laboratorio local
    6. Consentimiento informado por escrito firmado y fechado, de conformidad con las normas de buenas prácticas clínicas (BPC) de la ICH y la legislación local antes de la inclusión en el ensayo.
    E.4Principal exclusion criteria
    1. Massive confirmed pulmonary embolism (PE) with haemodynamic instability at trial entry
    2. Patients on mechanical ventilation for longer than 48 hours
    3. Chronic pulmonary disease i.e. with known forced expiratory volume in 1 second (FEV1) <50% requiring home oxygen, or oral steroid therapy or hospitalisation for exacerbation within 12 months, or significant chronic pulmonary disease in the Investigator’s opinion, or primary pulmonary arterial hypertension
    4. Has a Do-Not-Intubate (DNI) or Do-Not-Resuscitate (DNR) order
    5. In the opinion of the investigator, is not expected to survive for
    > 48 hours after admission
    6. Patients with known hypersensitivity to the active substance alteplase, gentamicin (a trace residue from the manufacturing process) or to any of the excipients
    7. Significant bleeding disorder at present or within the past 3 months, known haemorrhagic diathesis
    8. Patients receiving effective oral anticoagulant treatment, e.g. vitamin K antagonists with INR >1.3, or any direct oral anticoagulant within the past 48 hours
    9. Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery)
    10. History or evidence or suspicion of intracranial haemorrhage including sub-arachnoid haemorrhage
    11. Severe uncontrolled arterial hypertension (according to the investigator`s judgement)
    12. Major surgery or significant trauma in the past 10 days, recent trauma to head or cranium
    13. Cardiac arrest and/or cardiopulmonary resuscitation during the current hospital stay
    14. Obstetrical delivery within the past 10 days
    15. Severe hepatic dysfunction, including biopsy confirmed hepatic cirrhosis, portal hypertension, hepatic encephalopathy, or active hepatitis
    16. Bacterial endocarditis, pericarditis
    17. Acute pancreatitis
    18. Documented ulcerative gastro-intestinal disease during the last 3 months
    19. Severe heart failure (New York Heart Association Class IV)
    20. Arterial aneurysms, arterial/venous malformations
    21. Malignancy (Stage IV)
    22. Haemorrhagic stroke or stroke of unknown origin at any time
    23. Ischaemic stroke or transient ischaemic attack (TIA) in the preceding 6 months

    Further criteria apply.
    1. Embolia pulmonar (EP) masiva confirmada con inestabilidad hemodinámica en el momento de la inclusión en el ensayo
    2. Pacientes sometidos a ventilación mecánica durante más de 48 horas
    3. Enfermedad pulmonar crónica, es decir, con VEF1 <50 % que requiera oxígeno domiciliario, o tratamiento con corticoesteroides orales u hospitalización por reagudización en el plazo de 12 meses, o enfermedad pulmonar crónica significativa en opinión del investigador o hipertensión arterial pulmonar primaria
    4. Tener una orden de no intubar (NI) o no reanimar (NR)
    5. En opinión del investigador, no se espera que sobreviva más de 48 horas después del ingreso
    6. Pacientes con hipersensibilidad conocida a alteplasa, gentamicina (trazas de residuo del proceso de fabricación) u otros excipientes
    7. Trastorno hemorrágico significativo en la actualidad o en los últimos 3 meses, diátesis hemorrágica conocida
    8. Pacientes en tratamiento con anticoagulantes orales efectivos, p.ej. antagonistas de la vitamina K con un INR>1.3, o cualquier anticoagulante oral directo en las últimas 48 horas
    9. Cualquier historial de daño al sistema nervioso central
    10. Historia o evidencia o sospecha de hemorragia intracraneal incluyendo hemorragia subaracnoidea
    11. Hipertensión arterial severa y no controlada (de acuerdo al juicio del investigador)
    12. Cirugía mayor o trauma significante en los últimos 10 días, trauma reciente en la cabeza o en el cráneo
    13. Paro cardíaco y/o resucitación cardiopulmonar durante la estancia hospitalaria actual
    14. Parto obstétrico en los últimos 10 días
    15. Disfunción hepática severa, incluyendo cirrosis hepática confirmada con biopsia, hipertensión portal, encefalopatía hepática, o hepatitis activa
    16. Endocarditis bacteriana, pericarditis
    17. Pancreatitis aguda
    18. Enfermedad gastrointestinal ulcerativa documentada durante los últimos 3 meses
    19. Fallo cardíaco severo (New York Heart Association Clase IV)
    20. Aneurisma arterial, malformación venosa/arterial
    21. Neoplasia (Estadio IV)
    22. Accidente cerebrovascular hemorrágico o accidente cerebrovascular de origen desconocido en cualquier momento
    23. Accidente cerebrovascular isquémico o accidente isquémico transitorio en los 6 meses precedentes
    Se aplican otros criterios.
    E.5 End points
    E.5.1Primary end point(s)
    1) Time to clinical improvement or hospital discharge up to Day 28, defined as the time from randomization to either an improvement of two points on the 11-point WHO Clinical Progression Scale or discharge from the hospital, whichever comes first.
    1) Tiempo hasta la mejoría clínica o el alta hospitalaria hasta el día 28, definido como el tiempo transcurrido desde la aleatorización hasta una mejoría de dos puntos en la
    Escala de Progresión Clínica de la OMS de 11 puntos o el alta hospitalaria, lo que ocurra primero
    E.5.1.1Timepoint(s) of evaluation of this end point
    1) up to day 28
    1) hasta el día 28
    E.5.2Secondary end point(s)
    1) All cause mortality at Day 28
    2) Number of ventilator-free days from start of treatment to Day 28
    3) Improvement of Sequential (sepsis-related) Organ Failure Assessment (SOFA) score by ≥2 points from baseline to end of Day 6
    4) Major bleeding events (MBE) (according to International Society on Thrombosis and Haemostasis [ISTH] definition until Day 6
    5) Daily average PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change from baseline to Day 6
    6) All-cause mortality or on mechanical ventilation at Day 28
    1) Mortalidad por cualquier causa el día 28
    2) Número de días sin respirador desde el inicio del tratamiento al día 28
    3) Mejoría de la puntuación de la evaluación de la insuficiencia orgánica (SOFA) secuencial (relacionada con la septicemia) en ≥2 puntos desde el basal hasta el día 6
    4) Acontecimientos de hemorragia mayor (MBE) según la definición de la Sociedad Internacional de Trombosis y Hemostasia (ISTH) hasta el día 6
    5) Cambio medio diario del cociente PaO2/FiO2 (o cociente PaO2/FiO2 inferido del SpO2) des del basal hasta el día 6
    6) Mortalidad por cualquier causa o en ventilación mecánica el día 28
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) Day 28
    2) Day 28
    3) Day 6
    4) Day 6
    5) Day 6
    5) Day 28
    1) Día 28
    2) Día 28
    3) Día 6
    4) Día 6
    5) Día 6
    5) Día 28
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) 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
    standard of care
    E.8.2.4Number of treatment arms in the trial3
    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 EEA25
    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
    China
    Russian Federation
    United Kingdom
    Austria
    Belgium
    Denmark
    France
    Germany
    Italy
    Netherlands
    Portugal
    Spain
    Sweden
    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
    Última visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 10
    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: 2
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 178
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2023-10-11. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women Yes
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    patients can be under sedation or unconciouss
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state23
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 270
    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)
    None
    Ninguno
    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 Decision2020-12-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-12-14
    P. End of Trial
    P.End of Trial StatusCompleted
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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