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    Summary
    EudraCT Number:2020-005447-23
    Sponsor's Protocol Code Number:75871
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-28
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2020-005447-23
    A.3Full title of the trial
    A randomised, double-blind, placebo-controlled study to investigate the safety and efficacy of intravenous imatinib mesilate (Impentri®) in subjects with Acute Respiratory Distress Syndrome induced by COVID-19.
    Een gerandomiseerde, dubbel-geblindeerde, placebo-gecontroleerde studie naar de veiligheid en effectiviteit van intraveneus imatinib mesilate (Impentri®) in patienten met COVID-19 gerelateerd Acute Respiratory Distress Syndrome.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Intravenous imatinib for corona virus-related lung injury.
    Intraveneus imatinib voor corona virus-gerelateerde longschade.
    A.3.2Name or abbreviated title of the trial where available
    Intravenous imatinib for COVID-19-related ARDS.
    Intraveneus imatinib voor COVID-19-gerelateerd ARDS.
    A.4.1Sponsor's protocol code number75871
    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 SponsorAmsterdam Universitair Medische Centra, location VUmc
    B.1.3.4CountryNetherlands
    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 supportEuropean Union
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmsterdam Universitair Medische Centra, location VUmc
    B.5.2Functional name of contact pointDr. Jurjan Aman
    B.5.3 Address:
    B.5.3.1Street AddressDe Boelelaan 1117
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1081 HV
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+310204441896
    B.5.6E-mailj.aman@amsterdamumc.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1357
    D.3 Description of the IMP
    D.3.1Product nameImatinib (8 mg/mL) solution for infusion
    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 INNIMATINIB MESILATE
    D.3.9.1CAS number 220127-57-1
    D.3.9.3Other descriptive nameImatinib mesilate; imatinib mesylate; imatinib methanesulfonate;
    D.3.9.4EV Substance CodeSUB12517MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number8
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) 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 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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    COVID-19 related Acute Respiratory Distress Syndrome (ARDS) in mechanically-ventilated patients on the Intensive Care Unit.
    COVID-19-gerelateerd ARDS in mechanisch beademende patienten op de afdeling Intensive Care.
    E.1.1.1Medical condition in easily understood language
    Corona virus related lung injury.
    Corona virus-gerelateerde longschade.
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level LLT
    E.1.2Classification code 10084270
    E.1.2Term SARS-CoV-2 acute respiratory disease
    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 investigate the safety and effectiveness of imatinib mesilate solution for direct intravenous (iv) injection in mechanically-ventilated subjects with COVID-19-related ARDS.
    Onderzoek naar de veiligheid en effectiviteit van intraveneus imatinib mesilate in mechanisch beademde patiënten met COVID-19-gerelateerd ARDS.
    E.2.2Secondary objectives of the trial
    Not applicable.
    Niet van toepassing.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age ≥ 18 years;
    2. Moderate-severe ARDS, as defined by Berlin definition for ARDS, and intubated for mechanical ventilation.
    3. PCR positive for SARS-CoV2 within the current disease episode.
    4. Provision of signed written informed consent from the patient or patient's legally authorised representative;
    1. Leeftijd ≥ 18 jaar;
    2. Matig-ernstig ARDS, gedefinieerd door de Berlin criteria voor ARDS, en geintubeerd voor mechanische beademing.
    3. PCR positief voor SARS-CoV2 gedurende de huidige ziekte episode.
    4. Informed consent getekend door patient of wettelijke vertegenwoordiger
    E.4Principal exclusion criteria
    1. Persistent septic shock (>24h) with a Mean Arterial Pressure (MAP) ≤ 65 mm Hg and serum lactate level > 4 mmol/L (36 mg/dL) despite adequate volume resuscitation and vasopressor use (norepinephrine > 0.2 μg/kg/min) for > 6 hours;
    2. Pre-existing chronic pulmonary disease, including: o Known diagnosis of Interstitial Lung disease
    o Known diagnosis of COPD Gold IV or FEV1<30%pred o DLCO <45% (if test results are available)
    o Total lung capacity (TLC) < 60% of predicted (if test results are available);
    3. Chronic home oxygen treatment;
    4. Pre-existing heart failure with a known left ventricular ejection
    fraction <40%;
    5. Active treatment of haematological or non-haematological cancer with targeted immuno- or chemotherapy, or thoracic radiotherapy in the last year;
    6. Currently receiving extracorporeal life support (ECLS);
    7. Severe chronic liver disease with Child-Pugh score > 12;
    8. Subjects in whom a decision to withdraw medical care is made (e.g.
    palliative setting);
    9. Inability of the ICU staff to initiate study drug administration within 48 hours of screening;
    10. Known to be pregnant or breast-feeding;
    11. Enrolled in a concomitant clinical trial of an investigational
    medicinal product;
    12. White blood count < 2.5x109/l;
    13. Haemoglobin < 4.0 mmol/l;
    14. Thrombocytes < 50x109/l;
    15. The use of strong CYP3A4 inducers, including the following drugs:
    Carbamazepine, efavirenz, enzalutamide, fenobarbital, fenytoine, hypericum, mitotaan, nevirapine, primidon, rifabutine, rifampicine;
    1. Persisterende septische shock (>24 uur) met Mean Arterial Pressure (MAP) ≤ 65 mm Hg en serum lactaat > 4 mmol/L (36 mg/dL) ondanks adequate volume resuscitatie en vasopressie (noradrenaline > 0.2 μg/kg/min) voor > 6 uur;
    2. Pre-existente chronische longziekte, inclusief:
    o Interstitiele longziekte
    o COPD Gold IV of FEV1<30% of predicted
    o DLCO <45% (indien bekend)
    o Total lung capacity (TLC) < 60% of predicted (indien bekend)
    3. Chronische zuurstof therapie thuis
    4. Pre-existent hartfalen met ventriculaire ejectie
    fractie <40%;
    5. Active behandeling voor hematologische of niet-hematologische maligniteit met immuno- of chemotherapie, of thoracale radiotherapie in het laatste jaar;
    6. Patiënt ondergaat extracorporeal life support (ECLS);
    7. Ernstige chronische leverziekte (Child-Pugh score > 12);
    8. Patiënten met een palliatief beleid;
    9. Onvermogen van de IC staf om behandeling met de studiemedicatie binnen 48 uur na screening te starten
    10. Patiënte is zwanger of geeft borstvoeding;
    11. Patiënt is reeds in een andere medicijnenstudie geincludeerd;
    12. Leukocyten < 2.5x109/l;
    13. Hemoglobine < 4.0 mmol/l;
    14. Trombocyten < 50x109/l;
    15. Gebruik van sterke CYP3A4 inductoren, inclusief:
    Carbamazepine, efavirenz, enzalutamide, fenobarbital, fenytoine, hypericum, mitotaan, nevirapine, primidon, rifabutine, rifampicine;
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the change in extravascular lung water index (ΔEVLWi) between Day 1 (baseline) and Day 4, as measured by PICCO catheter.
    Verandering in extravasculair long water index (ΔEVLWi) tussen dag 1 (baseline) en dag 4, gemeten middels een PICCO catheter.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 1 (baseline), day 2, day 4 and day 7.
    Dag 1 (baseline), dag 2, dag 4 en dag 7.
    E.5.2Secondary end point(s)
    Pulmonary edema, gas-exchange and respiratory mechanics:
    • Extravascular Lung Water Index (Day 1, 2, 4 and 7)
    • Pulmonary vascular permeability index (Day 1, 2, 4 and 7)
    • Oxygenation index (Day 1, 2, 4, 7, 10 and Day 28, if available)
    • PaO2/FiO2 ratio (Day 1, 2, 4, 7, 10 and Day 28, if available)
    • Airway driving pressure (Day 1, 2, 4, 7, 10 and on Day 28, if available)
    • Compliance of the respiratory system (Day 1, 2, 4, 7, 10 and on Day 28, if available)
    • Mechanical power (Day 1,2,4,7,10 and on Day 28 if available)

    Inflammation, endothelial injury and lung epithelial injury:
    • Plasma biomarkers of inflammation, endothelial injury and lung epithelial injury (Day 1, 2, 4, 7 and 10)
    Organ function and outcome:
    • Sequential Organ Failure Assessment (SOFA) score (Day 1, 2, 4, 7, 10 and on Day 28, if available)
    • Number of ventilator-free days and alive at day 28
    • Duration of mechanical ventilation (days) till day 28
    • Length of ICU stay (days) till day 28
    • Hospital length of stay (days) till day 28
    • 28-day mortality

    Safety parameters
    o Blood cell count, i.e. haemoglobin, thrombocytes and leucocytes (Day 1,2,4,7 and 10)
    o Kidney function, estimated glomerular filtration rate, sodium and potassium (Day 1,2,4,7 and 10)
    o Liver enzymes, i.e. ASAT, ALAT, Alkaline Phosphatase, γ- glutamyltransferase, bilirubin (Day 1,2,4,7 and 10)
    o NT-proBNP (Day 1,2,4,7 and 10)
    o SAEs / AE
    o Corrected QT interval at ECG (Day 1,2,4,7 and 10)

    Pharmacokinetics
    o Study drug plasma levels at 4h and 8h after administration (Day 1) and on Day 2,4,7,10
    o In a subpopulation study drug plasma levels during administration and 2h after administration.
    o Albumin, AGP1 at 4h, 8h, Day 2,4,7 and 10.
    • Extravascular Lung Water Index
    • Pulmonary vascular permeability index
    • Oxygenatie index
    • PaO2/FiO2 ratio
    • Airway driving pressure
    • Compliance
    • Mechanical power
    • Plasma biomarkers van inflammatie en endotheel schade
    • Sequential Organ Failure Assessment score
    • Aantal dagen vrij van mechanische beademing tot dag 28
    • Duur van mechanische beademing in dagen
    • Duur van IC opname en ziekenhuis opname in dagen tot dag 28
    • 28-dagen mortaliteit
    • Bloedbeeld
    • Nierfunctie (kreatinine en eGFR) en leverfunctie (ASAT, ALAT, alkaline fofatase, γ-glutamyltransferase, bilirubine), natrium en kalium
    • NT-proBNP
    • SAEs / AE
    • Gecorrigeerd QT interval op ECG
    • Studie medicatie plasma levels
    • Albumine en AGP1
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Extravascular Lung Water and pulmonary vascular permeability Index: Day 1, 2, 4 and 7.
    - Other parameters of gas-exchange and respiratory mechanics: Day 1, 2, 4, 7, 10 and Day 28
    - Plasma biomarkers of inflammation, endothelial injury and lung epithelial injury: Day 1, 2, 4, 7 and 10
    - Sequential Organ Failure Assessment score: Day 1, 2, 4, 7, 10 and Day 28
    - Number of ventilator and ventilator-free days and alive: day 28
    - Length of ICU stay and length of hospital stay: day 28
    - Blood tests: Day 1,2,4,7 and 10
    - Study drug plasma levels at 4h and 8h after administration (Day 1) and on Day 2,4,7,10
    - Extravascular Lung Water en pulmonary vascular permeability Index: dag 1, 2, 4 en 7.
    - Andere parameters of gasuitwisseling en respiratoire mechanica: dag 1, 2, 4, 7, 10 en 28
    - Plasma biomarkers van inflammatie en endotheel schade: dag 1, 2, 4, 7 en 10
    - Sequential Organ Failure Assessment score: dag 1, 2, 4, 7, 10 en 28
    - Duur van mechanische beademing: dag 28
    - Duur van IC opname en ziekenhuis opname: dag 28
    - Bloedtesten: dag 1,2,4,7 en 10
    - Studie medicatie plasma levels: 4 en 8 uur na eerste toediening en op dag 2,4,7,10
    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 Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    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 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 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
    Laatste bezoek van de laatste studie deelnemer
    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 days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    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: 45
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 45
    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 No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    The trial will include patients who are intubated and mechanically ventilated, therefore unable to give informed consent. Informed consent will be obtained by the legal representative.
    De studie zal geintubeerde, mechanisch beademende patienten includeren. Informed consent zal worden verkregen van een wettelijke vertegenwoordiger.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state90
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients will continue receive usual supportive care appropriate to their stage of recovery from COVID-19.
    Patiënten zullen de standaard zorg ontvangen totdat het maximale herstel van de COVID-19 pneumonie bereikt is.
    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 Decision2021-01-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-01-22
    P. End of Trial
    P.End of Trial StatusOngoing
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