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    Summary
    EudraCT Number:2020-002913-16
    Sponsor's Protocol Code Number:0135-0347
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-11-05
    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 ConcernedBelgium - FPS Health-DGM
    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.
    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.
    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 SponsorSCS Boehringer Ingelheim Comm. V
    B.1.3.4CountryBelgium
    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 supportSCS Boehringer Ingelheim Comm. V
    B.4.2CountryBelgium
    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 number498002430127
    B.5.5Fax number498008217119
    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
    E.1.1.1Medical condition in easily understood language
    Severe breathing problems caused by 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.
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age ≥ 18 years (or above legal age)
    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 ≥ lower limit of normal
    5. D-Dimer ≥ 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.
    E.4Principal exclusion criteria
    1. Massive confirmed PE with haemodynamic instability at trial entry, or any (suspected or confirmed) PE that is expected to require therapeutic dosages of anticoagulants during the treatment period
    2. Indication for therapeutic dosages of anticoagulants at trial entry
    3. Mechanical ventilation for longer than 48 hours
    4. Chronic pulmonary disease i.e. with known 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
    5. Has a Do-Not-Intubate (DNI) or Do-Not-Resuscitate (DNR) order
    6. In the opinion of the investigator not expected to survive for > 48 hours after screening.
    7. Planned interventions during the first 5 days after randomization, such as surgery, insertion of central catheter or arterial line, drains, etc.
    8. Known hypersensitivity to the active substance alteplase, gentamicin (a trace residue from the manufacturing process) or to any of the excipients
    9. Significant bleeding disorder at present or within the past 6 months, known haemorrhagic diathesis
    10. 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
    11. Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery)
    12. History or evidence or suspicion of intracranial haemorrhage including sub-arachnoid haemorrhage
    13. Severe uncontrolled arterial hypertension (according to the investigator`s judgement)
    14. Major surgery or significant trauma in the past 10 days, recent trauma to head or cranium
    15. Cardiac arrest and/or cardiopulmonary resuscitation during the current hospital stay
    16. Obstetrical delivery within the past 10 days
    17. Severe hepatic dysfunction i.e. Child-Pugh B and C, including biopsy confirmed hepatic cirrhosis, portal hypertension, hepatic encephalopathy, or active hepatitis
    18. Bacterial endocarditis, pericarditis
    19. Acute pancreatitis
    20. Documented ulcerative gastro-intestinal disease during the last 3 months
    21. Severe heart failure (New York Heart Association Class IV)
    22. Arterial aneurysms, arterial/venous malformations
    23. Malignancy (Stage IV) with increased bleeding risk

    Further criteria apply.
    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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1) up to day 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] definitin 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
    7. Treatment failure defined as all cause mortality or mechanical ventilation at Day 28
    8. Number of oxygen-free days up to Day 28
    9. Length of hospital stay up to Day 28
    10. PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change from baseline to Day 6


    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
    6) Day 28
    7) Day 28
    8) Day 28
    9) Day 28
    10) Day 6
    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 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA38
    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
    Australia
    Brazil
    Colombia
    Egypt
    India
    Mexico
    Russian Federation
    South Africa
    Tunisia
    Turkey
    Austria
    Belgium
    Denmark
    France
    Germany
    Italy
    Poland
    Portugal
    Netherlands
    Romania
    Spain
    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
    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 months9
    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: 8
    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: 250
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    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 2020-11-05. 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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 320
    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
    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 Decision2020-11-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-11-26
    P. End of Trial
    P.End of Trial StatusOngoing
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