E.1 Medical condition or disease under investigation |
E.1.1 | Medical 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. |
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E.1.1.1 | Medical condition in easily understood language |
Corona virus related lung injury. |
Corona virus-gerelateerde longschade. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10084270 |
E.1.2 | Term | SARS-CoV-2 acute respiratory disease |
E.1.2 | System Organ Class | 100000004862 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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.
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Onderzoek naar de veiligheid en effectiviteit van intraveneus imatinib mesilate in mechanisch beademde patiënten met COVID-19-gerelateerd ARDS. |
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E.2.2 | Secondary objectives of the trial |
Not applicable. |
Niet van toepassing. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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;
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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 |
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E.4 | Principal 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; |
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(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. |
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E.5.2 | Secondary 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 |
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E.5.2.1 | Timepoint(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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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LVLS |
Laatste bezoek van de laatste studie deelnemer |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |