E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute respiratory distress syndrome (ARDS) caused by COVID-19 |
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E.1.1.1 | Medical condition in easily understood language |
Severe respiratory illness caused by the coronavirus |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
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 |
1. Efficacy: Investigate the potential for efficacy of nebulised rtPA in patients presenting with severe COVID-19 requiring IMV or Non-invasive support with NIV OR continuous positive airway pressure (CPAP) OR high flow oxygen Or standard oxygen therapy 2. Safety: Evaluate the safety of nebulised rtPA treatment.
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E.2.2 | Secondary objectives of the trial |
1. Investigate the impact on patient’s clinical status over time using the WHO ordinal scale of clinical improvement. 2. Investigate the effect of nebulised rtPA on other respiratory markers (such as lung compliance) and organ dysfunction 3. Investigate the impact on in hospital mortality and resource utilisation
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
All treatment group patients must meet the following criteria (ward or ICU based): 1. Patients with COVID-19 (confirmed by PCR or radiologically) 2. ≥16 years 3. Willing and able to provide written informed consent or where patient doesn’t have capacity, consent obtained from a legal representative 4. Patients on IMV must meet both the following criteria: a. PaO2/FiO2 of ≤ 300 b. Intubated > 6 hrs 5. Patients not intubated must meet all the following criteria: a. PaO2/FiO2 ≤ 300 or equivalent imputed by non-linear calculation from SpO2/FiO2 (see look-up table in appendices) b. In-patient >6hours and being actively treated c. On support with non-invasive ventilation OR continuous positive airway pressure (CPAP) OR high flow OR standard oxygen therapy
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E.4 | Principal exclusion criteria |
None of the following criteria must apply: 1. Females who are pregnant 2. Concurrent involvement in another experimental investigational medicinal product 3. Known allergies to the IMP or excipients of IMP 4. A pre-existing bleeding disorder with no definitive treatment (e.g. severe haemophilia) 5. Pre-existing severe cardiopulmonary disease (e.g. incurable lung cancer, severe chronic obstructive lung disease, cardiomyopathy, heart failure or impaired contractility <estimated 40% LVEF or RVEF) 6. Fibrinogen < 2.0 g/L at time of screening 7. Patients considered inappropriate for active treatment (e.g. being considered for palliative care) 8. Patients with active bleeding in the preceding 7 days 9. Patients who in the opinion of the investigator are not suitable
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy 1. Change in PaO2/FiO2 ratio from baseline (3 days prior to treatment), daily during treatment, end of treatment and 3 and 5 days post treatment in the groups receiving rtPA
Safety 1. Incidence and severity of major bleeding events directly attributable to the study drug 2. Decrease in fibrinogen levels to < 1.5 gm/L during treatment period and 48 hrs after the last dose of treatment 3. Number and nature of serious adverse events causally related to the treatment
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy - daily during treatment, end of treatment and 3 and 5 days post treatment Safety - every day of trial (and as indicated in each primary outcome measure) |
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E.5.2 | Secondary end point(s) |
1. Changes in lung compliance (defined as mL/cm H₂O VT / ( PIP – PEEP )) from baseline (3 days prior to treatment) and absolute values at day 5, day 7, end of treatment, 3 days post end of treatment and 5 days post end of treatment 2. Clinical status as assessed by a 7-point WHO ordinal scale at baseline (3 days prior to treatment), daily up to 5 days post end of treatment and at day 28, discharge or death (whichever comes first) 3. Mean daily Sequential Organ Failure Assessment (SOFA) score at baseline (3 days prior to treatment) and daily up to 5 days post end of treatment. 4. In follow up period, number of oxygenation free days, ventilator free days, intensive care stay, up to 28 days or death or discharge, whichever occurs first. 5. Incidence and number of days of new oxygen use, non-invasive ventilation or high flow oxygen devices in the first 28 days. 6. Incidence and number of days of new mechanical ventilation use during in the first 28 days 7. In hospital mortality
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints for evaluation are as indicated in each secondary endpoint |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.1.7.1 | Other trial design description |
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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 |
standard of care arm alone (use of historical controls) |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 2 |
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 | No |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
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 |