E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute respiratory distress syndrome caused by Covid-19 |
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E.1.1.1 | Medical condition in easily understood language |
Severe breathing problems caused by Covid-19 |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10001052 |
E.1.2 | Term | Acute respiratory distress syndrome |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 evaluate the efficacy and safety of intravenous alteplase in ARDS triggered by COVID-19. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.
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E.4 | Principal 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.
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary 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
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E.5.2.1 | Timepoint(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
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | Yes |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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 |
South Africa |
Tunisia |
Austria |
France |
Poland |
Netherlands |
Romania |
Spain |
Germany |
Italy |
Belgium |
Denmark |
Portugal |
Russian Federation |
Turkey |
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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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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 | |
E.8.9.1 | In the Member State concerned days | 6 |
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 | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |