Intravenous Imatinib in Mechanically Ventilated COVID-19 Patients
Intravenous Imatinib in Mechanically Ventilated COVID-19 Patients
The SARS-CoV2 pandemic and resulting COVID-19 infection has led to a large increase in the
 number of patients with acute respiratory distress syndrome (ARDS). ARDS is a severe,
 life-threatening medical condition characterised by inflammation and fluid in the lungs.
 There is no proven therapy to reduce fluid leak, also known as pulmonary oedema, in ARDS.
 However, recent studies have discovered that imatinib strengthens the cell barrier and
 prevents fluid leak in the lungs in inflammatory conditions, while leaving the immune
 response intact. The investigators hypothesize that imatinib limits pulmonary oedema observed
 in ARDS due to COVID-19, and may thus help to reverse hypoxemic respiratory failure and to
 hasten recovery.

 The hypothesis will be tested by conducting a randomised, double-blind, parallel-group,
 placebo-controlled multi-centre clinical study of intravenous imatinib in 90
 mechanically-ventilated, adult subjects with COVID-19-related ARDS.

 Study participants will receive the study drug (imatinib or placebo) twice daily for a period
 of 7 days. The effect of the intervention will be tested by measuring extravascular lung
 water (i.e. pulmonary oedema) difference between day 1 and day 4, using a PiCCO catheter (=
 pulse contour cardiac monitoring device).

 Other measurements will include regular blood tests to investigate the safety and the
 pharmacokinetic properties of imatinib, as well as biomarkers of inflammation and cellular
 dysfunction. Furthermore, parameters of ventilation and morbidity and mortality will be
 recorded as secondary outcome measures.
1. INTRODUCTION

 1.1 Background of ARDS due to COVID-19

 The COVID-19 pandemic has led to an unanticipated increase of the number of patients
 with ARDS admitted to the ICU, contributing to high morbidity and mortality, as well as
 an unprecedented consumption of medical resources. COVID-19 is caused by a coronavirus
 (scientific name: SARS-CoV-2), a non-segmented, positive sense RNA virus. Although most
 SARS-CoV-2 infections have an asymptomatic or mild course of disease (80%), COVID-19 has
 a detrimental course in a minority of patients (20%), particularly in older patients or
 patients with pulmonary or cardiovascular comorbidities. In these cases, COVID-19
 infection is characterized by damage to the alveolocapillary wall and extensive
 pulmonary capillary leak. The alveolar flooding results in impairment of oxygen
 diffusion and severe hypoxemic respiratory failure. In Chinese registries these cases of
 COVID-19 disease were classified as either 'severe' in case of low oxygen saturation or
 'critical' when invasive mechanical ventilation was needed or multi-organ failure
 occurred. Radiological imaging demonstrates extensive ground glass opacities, consistent
 with alveolar oedema.

 Radiological as well as pathological examination demonstrated that critical COVID-19
 infections closely mimic Acute Respiratory Distress Syndrome (ARDS), a condition
 characterized by damage to the alveolo-capillary membrane by various insults. Mortality
 in ICU treated 'critical' COVID-19 patients is comparable to mortality in ARDS patients.
 Of the patients admitted with COVID-19 infection to hospital, 17-35% develop ARDS,
 requiring ICU admission or even invasive mechanical ventilation (29-91%). According to
 recent reviews, mortality may mount up to 15-20% (hospitalized patients) to even 40% in
 ICU patients. For these reasons, the current COVID-19 pandemic has resulted in a huge
 increase in the incidence of ARDS with a homogenous aetiology i.e., SARS-CoV2 infection.

 According to the Berlin definition, ARDS is '…an acute diffuse, inflammatory lung
 injury, leading to increased pulmonary vascular permeability, increased lung weight, and
 loss of aerated lung tissue…[with] hypoxemia and bilateral radiographic opacities,
 associated with increased venous admixture, increased physiological dead space and
 decreased lung compliance'. It is characterised by an acute onset, with bilateral
 infiltrates on chest imaging due to pulmonary oedema, and with severe hypoxemia despite
 mechanical ventilation. Pathophysiologically, ARDS results from an overwhelming
 inflammatory process involving alveolar epithelial and vascular endothelial injury in
 the lung which can be infective and non-infective in origin. The early phase of ARDS is
 characterized by alveolar flooding with protein-rich fluid due to increased vascular
 permeability. Pulmonary oedema then leads to the clinical manifestation of poor lung
 compliance, severe hypoxaemia, and bilateral inﬁltrates on chest radiograph. It also
 leads to alveolar epithelial injury of type I cells, which contributes further to the
 pulmonary oedema. Despite decades of efforts, there is currently no registered drug to
 target pulmonary vascular permeability in ARDS.

 Current treatment of patients with 'critical' COVID-19 consists of supportive measures,
 including oxygen supplementation, diuretics and (non)-invasive mechanical ventilation.
 Current guidelines prescribe dexamethasone and remdesivir for patients with hypoxemia.
 Although remdesivir and dexamethasone target key pathophysiological processes of
 COVID-19 like viral replication and inflammatory damage, respectively, there is
 currently no proven benefit of pharmacological intervention to reverse pulmonary
 vascular leak and oedema.

 1.2 Rationale for intervention Earlier studies demonstrate that the anti-leukemic drug
 imatinib effectively and consistently protects against pulmonary vascular leak and
 alveolar oedema during inflammatory stimuli. In 2008, a patient with acute respiratory
 failure due to widespread pulmonary oedema was treated with imatinib mesylate for
 another indication than the acute respiratory failure itself. However, initiation of the
 imatinib treatment (200mg/day) was followed by a surprisingly fast reversal of
 respiratory failure. The reversal of respiratory failure was paralleled by decrease in
 pulmonary oedema on radiological imaging, resulting in the hypothesis that imatinib
 directly protects the pulmonary endothelial barrier. This unexpected effect of imatinib
 was published in 2008. The hypothesis was tested in an extensive preclinical study,
 evaluating the effect of imatinib on endothelial barrier function in several conditions.
 These studies demonstrated that imatinib protects the endothelial barrier under
 inflammatory conditions, both in in vitro models using several types of endothelial
 cells and various inflammatory mediators, and in vivo, using various animal models for
 vascular leak. The protective effects of imatinib were confirmed by several studies by
 independent research groups.

 After the publication of the first case report and the preclinical evidence for a
 protective effect of imatinib on the endothelial barrier, imatinib (300mg/day) was
 associated with clinical improvement of acute respiratory failure in 1 patient in an
 independent hospital. In addition, imatinib has been used in a compassionate use setting
 in 2 additional patients in the investigators' hospital - in both cases initiation of
 imatinib therapy (200-400mg/day) was followed by reversal of vascular leak and/or
 respiratory failure. Although these cases should be interpreted with caution, they
 consistently suggest a beneficial effect of imatinib on pulmonary vascular leak and/or
 respiratory failure. To date, one case report using oral imatinib to successfully treat
 COVID-19 pneumonia has been published. The protective effects of imatinib at the
 endothelial level 2-10μM were found at concentrations that are comparable to plasma
 levels found in patients treated with imatinib for CML (2-5μM), indicating that regular
 dosing schemes of imatinib are sufficient to induce its protective effect on the
 endothelial barrier. Indeed, preliminary data from the COUNTER-COVID study, which
 evaluates the effect of oral imatinib mesylate in hospitalized patients with COVID-19,
 demonstrate that dosing of 400mg/day orally is sufficient to reach target levels
 described above.

 Based on the observations that the optimal protective effect of imatinib on the
 endothelial barrier ranges between 2-10μM, together with previous pharmacokinetic
 studies after intravenous imatinib, the investigators propose a dosing scheme of 200mg
 b.i.d. This dosing scheme was shown to provide plasma levels that correspond to the
 2-10μM range found in prior in vitro studies. The current study will evaluate the effect
 of intravenous imatinib on pulmonary oedema as measured by EVLWi. Several arguments
 drive the use of intravenous imatinib in the current study: 1) since most ICU patients
 are intubated, oral administration is suboptimal. 2) Intestinal uptake in mechanically
 ventilated ICU patients is often impaired due to intestinal oedema. 3) by intravenous
 administration, imatinib directly reaches the target organ, i.e., the endothelium,
 requiring lower dosing and fewer side-effects. A detailed analysis on dosing and route
 of administration is provided in the Investigators Brochure.

 Concerning safety, imatinib was shown to have mild or no effects on the immune response.
 Although developed to target leukemic cells, imatinib hardly affects healthy leucocytes
 and a normal lymphocytic response was observed in lymphocytes from patients treated with
 imatinib. Of particular relevance for the current protocol, it was shown that treatment
 with imatinib does not affect the control of primary viral infections. The investigators
 demonstrated in a healthy volunteer model of lung injury that imatinib did not affect
 the immune response to LPS inhalation in healthy human subjects. Finally, the first
 interim analysis of the COUNTER-COVID study, which tests oral imatinib in COVID-19
 patients admitted to hospital with hypoxemia, did not reveal safety concerns after
 inclusion of the first 140 patients.

 Altogether, substantial evidence indicates that imatinib is an ideal candidate for
 treatment of the pulmonary complications of SARS-CoV2 like ARDS, since it protects
 against vascular leak and alveolar oedema thereby reducing hypoxemic respiratory
 failure. The current study seeks to directly measure the effect of intravenous imatinib
 on pulmonary vascular leak in COVID-19 ARDS. COVID-19 offers a homogenous cause of ARDS,
 however, the available evidence indicates that ARDS due to other causes will respond
 similarly to imatinib. Therefore, the identification of a compound that reverses
 pulmonary vascular leak may benefit well beyond COVID-19 ARDS and provide a first
 treatment for other forms of ARDS as well.

 2. OBJECTIVES

 Primary:

 -  Efficacy: To evaluate the effect of intravenous imatinib compared to standard of
 care on limiting development of extravascular lung water in invasively
 mechanically-ventilated subjects with COVID-19-related ARDS.

 Secondary:

 -  Efficacy: To evaluate the effect of intravenous imatinib compared to standard of
 care on patient outcomes in mechanically-ventilated subjects with COVID-19-related
 ARDS.

 -  Safety: To evaluate the safety and tolerability of intravenous imatinib compared to
 standard of care in mechanically-ventilated subjects with COVID-19-related ARDS

 -  Pharmacokinetics: To determine imatinib pharmacokinetics in subjects with
 COVID-19-related ARDS.

 3. STUDY DESIGN This is a randomised, double-blind, parallel-group, placebo-controlled,
 multi-centre clinical study comparing intravenous imatinib mesylate with placebo in
 invasively mechanically-ventilated subjects with COVID-19-related ARDS. The study will
 enrol 90 subjects (45 subjects/treatment arm; see sample size calculation). In this
 two-arm study, eligible subjects will be randomly allocated to receive imatinib mesylate
 or placebo in a 1:1 ratio. Importantly, the inclusion will be extended to all-cause ARDS
 if recruitment drops to below a predefined threshold (see inclusion criteria). Besides
 the randomisation to treatment of placebo, all subjects will be cared for using local
 treatment protocols as standard of care. At each of the participating centres, standard
 treatment protocols may include: COVID-19-specific medication (e.g. remdesivir and
 dexamethasone), low tidal volume ventilation, conservative fluid management and prone
 positioning in case of persistent low PaO2/FiO2.

 For eligibility criteria and outcome measures, see separate section.

 4. SAMPLE SIZE CALCULATION The number of subjects scheduled for inclusion in the study is
 90, including 45 subjects in the placebo arm and 45 subjects in the imatinib mesylate
 arm.

 Sample size calculations were done with the formula: zα/2 - zπ = (n/2)1/2 * (μ1 - μ2)/σ,
 in which zα/2-zπ = 2,8 (α = 5% en π = 80%). The change (Δ) in EVLWi between Day 0 and
 Day 4 is the primary outcome. The investigators expect the baseline EVLWi to be around
 17ml/kg, as previously described for patients with moderate-severe ARDS. In the placebo
 group the ΔEVLW Day 0 and Day 4 is expected to be 0.5 (μ1), based on previously
 literature from collaborating groups; in the imatinib group the ΔEVLWi is expected to be
 -4 (μ2). This is considered a clinically relevant difference as this difference was
 found to independently predict ARDS mortality in another clinical study. The expected
 treatment effect is based on the imatinib effect observed in preclinical data: 25%
 reduction in vascular leak. The sigma (σ) for ΔEVLWi is set at 7.0, based on previous
 EVLWi studies. Using the equation above, this yields 76 subjects with 38 subjects/arm.
 Taking into account a drop-out rate of 15%, a total of 90 subjects will be recruited.

 5. TREATMENT OF SUBJECTS

 5.1 Investigational product/treatment Subjects will undergo 1:1 randomisation to receive
 intravenous imatinib (200mg bid) or placebo for 7 days.

 5.2 Interactions Imatinib is a substrate for CYP3A4 and P-gp. It inhibits CYP3A4, CYP2D6
 and CYP2C9.

 Most relevant interactions for the study population include:

 • Strong induction of CYP3A4. The following drugs are contra-indicated for the study:
 Carbamazepine, efavirenz, enzalutamide, phenobarbital, phenytoin, hypericum, mitotane,
 nevirapine, primidone, rifabutin, rifampicin.

 -  CYP3A4 inhibition. In general, imatinib is relatively insensitive to CYP3A4
 inhibition, as imatinib may rely on enzymes other than CYP3A4 for its metabolism.
 Therefore, there is no need for adjustment, but recording of the following drugs in
 the eCRF is important: azoles.

 -  Imatinib may change the concentration of other CYP3A4, CYP2D6 and CYP2C9-dependent
 drugs, including anticoagulants, cyclosporine, simvastatin etc. All relevant
 co-medication will be registered.

 6. INVESTIGATIONAL PRODUCT

 6.1 Dosage and Administration A 25ml volume of IMP will be administered over 2-hours as
 an intravenous infusion. This corresponds to a dose of 200mg imatinib (100mg/h), or 25ml
 placebo (12.5ml/h). Treatment will be administered twice daily (400 mg total daily
 imatinib dose) for up to 7 days, or until patient is discharged from critical care, if
 earlier. The first dose of IMP will occur on Day 1, as soon as possible after
 randomisation. IMP should be administered 12h (± 2h) apart between 06:00 - 10:00 in the
 morning and 18:00 - 22:00 in the evening. On Day 1, the first dose of IMP may be
 administered between 04:00 and 12:00 (08:00± 4h) and the second dose between 16:00 and
 24:00 (20:00± 4h). Patients commencing treatment after 12:00 on Day 1 should receive
 only one dose of IMP (between 16:00 and 24:00).

 7. Randomisation, blinding and treatment allocation Randomisation: Before randomisation,
 the study physician will check all inclusion and exclusion criteria and will enters
 these in the web-based application (Castor). Screening and placement of the PiCCO
 catheter is performed as part of a deferred consent procedure. For subjects who meet the
 eligibility criteria, the patient's legal representative will be asked for informed
 consent(§11.2.2). When informed consent is provided, subjects will be randomized 1:1 to
 receive placebo or imatinib. Randomisation will take place via Castor using variable
 block sizes with stratification per participating centre. The pharmacist will check
 relevant drug interactions before dispensing medication.

 Blinding: Subjects, clinical staff and investigators will be blinded for study
 medication. Blinding will be guaranteed be covering the syringes containing the IMP so
 that the content will not be visible from the outside.

 Code breaking is allowed in any of the following circumstances:

 • Treatment of an individual in a medical emergency where knowledge of the treatment
 allocation is required.

 • In the event of a Suspected Unexpected Serious Adverse Reaction (SUSAR) the subject
 will be unblinded, if this is required for treatment of the SUSAR.

 • In the event that the ICU staff / researcher is accidentally exposed to study
 medication.

 8. SAFETY REPORTING

 8.1 Temporary halt for reasons of subject safety In accordance to section 10, subsection
 4, of the WMO, the sponsor may suspend the study if there are sufficient grounds that
 continuation of the study will jeopardise subject health or safety. The sponsor will
 notify the accredited METC without undue delay of a temporary halt including the reason
 for such an action. The study will be suspended pending a further positive decision by
 the accredited METC. The investigator will take care that all subjects are kept
 informed.

 8.2 AEs, SAEs and SUSARs: Due to the nature of disease, the incidence of AEs and SAEs,
 as well as the risk of death due to the underlying condition is high (the hospital
 mortality in ventilated ICU patients is 21%). In clinical studies conducted in patients
 with ARDS, changes in vital parameters are frequent, including temporary changes in
 blood pressure and gas exchange parameters, as are deviations in laboratory values and
 ECG values.

 AE Reporting:

 Given the high incidence of adverse events inherent to the nature of the underlying
 condition (i.e., ARDS), given the safety of imatinib as observed in COVID-19 pneumonitis
 before (COUNTER-COVID study), and given the regular recording of vital signs and blood
 and ECG parameters as safety indicators in the eCRF, the investigators propose not to
 report AEs in a standard fashion, except for the following events:

 • Pulmonary embolism, as detected on contrast enhance chest CT, not leading to
 circulatory of pulmonary instability.

 • Occurrence of infections, requiring initiation of antibiotic therapy

 • Non-life-threatening infusion reactions, including but not limited to skin rash.

 SAE Reporting:

 Given the high incidence of adverse events inherent to the nature of the underlying
 condition (i.e., ARDS), and given the safety of imatinib as observed in COVID-19
 pneumonitis before (COUNTER-COVID study), the investigators propose not to report all
 serious events as SAEs.

 The following SAEs will be reported:

 • Death due to any cause

 • Cardiopulmonary: The need for extracorporeal membrane oxygenation; Cardiac events like
 arrythmias requiring CPR or medical resuscitation; Thrombo-embolic events with
 life-threatening circulatory or pulmonary instability

 • Spontaneous bleeding, requiring blood transfusion or surgical intervention.

 • Myocardial infarction

 • Renal: the need for renal replacement therapy

 • Hepatic: Liver failure (hepatic SOFA score >4)

 • Haematology: Thrombocytopenia (<50^109/L), diffuse intravascular coagulation,
 leukocytopenia (<2^109/L), anaemia (haemoglobin <4mmol/L).

 -  Central Nervous System: Intracranial bleeding or ischemic stroke.

 -  Life-threatening infusion reactions, requiring intensification of existing
 intensive care treatment, including additional vasopressor, fluid support,
 corticosteroids and antihistamines.

 -  Any unexpected serious event judged as an "untoward medical occurrence".

 Reporting of Suspected unexpected serious adverse reactions (SUSARs):

 -  SUSARs that have arisen during this clinical trial that was assessed by the METC;

 -  SUSARs that have arisen in other clinical trials of the same sponsor and with the
 same medicinal product, and that could have consequences for the safety of the
 subjects involved in this clinical trial that was assessed by the METC.

 10. STATISTICAL ANALYSIS The statistical analysis will be performed using the program SPSS
 version 22.0 or R. Continuous data will be tested for normal distribution using a
 Kolmogorov-Smirnov test. In case of normal distribution, continuous data will be presented as
 mean ± standard deviation, in case of non-normal distribution, continuous data will be
 presented as median ± interquartile (IQR) range. Categorical data will be presented as
 absolute number (%). The continuous variables and the categorical data will be presented
 quantitatively in tables and in figures. Missing data will be accepted after maximal efforts
 to retrieve data.

 10.1 Primary study parameter(s) The primary endpoint is the change in extravascular lung
 water index (ΔEVLWi) between Day 1 (baseline) and Day 4. The primary endpoint will be
 represented mean ± standard deviation, in case of non-normal distribution, continuous data
 will be presented as median ± interquartile (IQR) range, and tested for statistical
 difference using a t-test or a Mann-Whitney U test in case of non-normal distribution. In
 addition, ANCOVA analysis will be performed.

 10.2 Secondary study parameter(s) For all parameters, statistical comparison will be
 performed between placebo and imatinib group.

 Plasma concentrations of imatinib at Ctrough will be described by descriptive statistics,
 including mean, SD, minimum, maximum, and median.

 11. ETHICAL CONSIDERATIONS 11.1 Regulation statement The general principles of informed
 consent, ethics review and data management will be in line with good clinical practice (GCP).
 The study will be conducted according to the principles of the Declaration of Helsinki (2013)
 and in accordance with the Medical Research Involving Human Subjects Act (WMO).

 11.2 Recruitment and consent 11.2.1 Recruitment Subjects will be recruited on the emergency
 units of the AUMC, locations AMC and VUMC, and the Onze Lieve Vrouwe Gasthuis, location
 Amsterdam Oost. Two additional centres are under consideration. With a minimum of 5 active
 centres and an anticipated duration of the trial of 18 months, and a target number of
 inclusions of 90 subjects, this means that 90/5=18 subjects per centre need to be enrolled,
 which amounts to <0.25 subjects/centre/week. When considering the AMC and VUMC as
 representative hospitals, the required rate of inclusion/centre is far below the current rate
 of presentations/centre.

 11.2.2 Deferred consent For this trial deferred consent is asked and the investigators appeal
 to the emergency procedure for consent in medical research as stated in article 6, paragraph
 4 of the WMO, similar to a presently running trial of ventilation in a similar patient
 cohort, the 'REstricted versus Liberal positive end-expiratory pressure in patients without
 Acute respiratory distress syndrome (RELAx)' - a multicenter randomized controlled trial
 (NL60402.018.17).

 Pulmonary vascular leak is a phenomenon that is observed early in the course of ARDS.
 Previously, an early 'exudative' phase (the first 3-5 days in the course of ARDS) was
 distinguished from a 'reorganising/proliferative' phase (Day 5 and further in the course of
 disease). Although this distinction is formally abandoned, it is generally accepted that the
 early course of ARDS is characterised by pulmonary vascular leak and alveolar exudates, in
 which the pulmonary oedema is the main cause of hypoxemia. Based on preclinical and early
 clinical data there is a reasonable chance that patients will benefit from the
 vasculoprotective effect of imatinib, especially in the early, exudative phase. The short
 extent of this exudative phase in time (days) indicates a limited window-of-opportunity to
 apply therapies directed at preserving or restoring the alveolocapillary barrier. For this
 reason, the investigators consider it of utmost importance to initiate the vasculoprotective
 treatment with imatinib as soon as possible (i.e., within 48 hours after ICU admission), not
 doing so would largely reduce validity of this trial. Additionally, the potential benefit
 from the intervention (which would not be available outside of given trial) is likely highest
 in the early phases.

 Subjects admitted to the ICU with ARDS are, without exception, incompetent to give informed
 consent. Persons who may take the role of legal representative in accordance with the WGBO
 are: a predefined representative, husband or wife, registered partner or other life partner,
 a parent or child, brother or sister, and incidentally a curator appointed the judge.
 However, obtaining informed consent from a legal representative in this situation usually
 takes much time, even by an experienced research team (see Textbox A). Reasons include the
 absence of a legal representative within the first 48h after admission, and early after
 admission to the ICU the legal representatives are far more concerned about the wellbeing of
 the patient then participation in a trial.

 For these reasons, the investigators opt for using deferred consent, where informed consent
 from a legal representative must be obtained as soon as possible, but always within 48 hours
 after intubation. While awaiting deferred consent, subjects will undergo screening and first
 baseline measurements. A PiCCO catheter will be placed (if not already in place), and the
 baseline EVLW and PCP measurement, as well as thoracic ultrasound in a subpopulation will be
 performed. The placement of a central venous catheter is part of standard care in intubated
 subjects. When deferred consent is provided the patient will continue study participation by
 randomisation and administration of the first IMP dose. When deferred consent is not obtained
 due to absence of a legal representative in the first 48 hours, or if a legal representative
 denies participation within the time window of 48 hours, the patient will not be enrolled and
 screening data will no longer be used. In that case, the PiCCO catheter will be used as
 arterial line as part of standard care, resulting in no net additional study procedures on
 top of standard care with the exception of the procedures needed to assess eligibility for
 the study.

 Further consent will be sought from the patient if they recover sufficiently and regain
 decision-making capacity while in hospital.

 11.2.3 No consent in subjects who die before obtaining deferred consent In case a patient
 dies before informed consent could be obtained from the legal representative, the
 investigators propose that the data collected during screening and at baseline will no longer
 be used. This will be recorded as a screening failure, and the reason for failure will be
 recorded.

 11.2.4 Conclusion deferred consent Critically ill subjects in need of ventilation are,
 without exception, incapable to give informed consent at the moment of ICU admission. Patient
 screening, eligibility checking and placing the PICCO catheter instead of a "normal arterial
 line" are part of the study procedures but cannot wait until informed consent is obtained
 from a legal representative. Therefore, a deferred consent procedure is relevant for the
 current study. IStudy medication will only be administrered after informed consent.

 11.2.5 Consent procedure

 The recruitment of study subjects is as follows:

 1. Approach of subjects (if patient is a candidate for study participation)

 1. In cases where a legal representative is present / accessible at ICU admission:

 The treating physician asks the legal representative if they would consider
 participation in a clinical trial for which they may be eligible and obtains their
 permission, for a member of the study team to contact them

 2. If their legal representative is not present / accessible at ICU admission:

 The treating physician contacts the study team who initiate the deferred consent
 procedure. During the deferred consent period, a member of the study team will regularly
 attempt to contact the patient's legal representative to obtain consent.

 2. Informed consent The investigator gives the patient information and consent statement to
 the patient's legal representative answering any questions about the study they may have
 and providing additional information when requested. The legal representative has at
 least 6 hours to read and consider whether to provide consent. The informed consent form
 is signed within 48 hours from ICU admission.
Inclusion Criteria:

 -  Age ≥ 18 years;

 -  Moderate-severe ARDS, as defined by Berlin definition for ARDS (onset within 1 week of
 a known clinical insult or new or worsening respiratory symptoms, bilateral opacities
 not fully explained by effusions, lobar/lung collapse, or nodules, respiratory failure
 not fully explained by cardiac failure or fluid overload and P/F ratio ≤200 mmHg with
 PEEP ≥5 cmH2O), and intubated for mechanical ventilation.

 -  PCR positive for SARS-CoV2 within the current disease episode.

 -  Provision of signed written informed consent from the patient or patient's legally
 authorised representative;

 Exclusion Criteria:

 -  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;

 -  Pre-existing chronic pulmonary disease, including:

 -  Known diagnosis of Interstitial Lung disease

 -  Known diagnosis of COPD GOLD Stage IV or FEV1<30% predicted

 -  DLCO <45% (if test results are available)

 -  Total lung capacity (TLC) < 60% of predicted (if test results are available);

 -  Chronic home oxygen treatment;

 -  Pre-existing heart failure with a known left ventricular ejection fraction <40%;

 -  Active treatment of haematological or non-haematological cancer with targeted immuno-
 or chemotherapy, or thoracic radiotherapy in the last year;

 -  Currently receiving extracorporeal life support (ECLS);

 -  Severe chronic liver disease with Child-Pugh score > 12;

 -  Subjects in whom a decision to withdraw medical care is made (e.g. palliative
 setting);

 -  Inability of the ICU staff to initiate IMP administration within 48 hours of
 intubation;

 -  Known to be pregnant or breast-feeding;

 -  Enrolled in a concomitant clinical trial of an investigational medicinal product;

 -  White blood count < 2.5x109/l;

 -  Haemoglobin < 4.0 mmol/l;

 -  Thrombocytes < 50x109/l;

 -  The use of strong CYP3A4 inducers, including the following drugs:

 -  Carbamazepine, efavirenz, enzalutamide, fenobarbital, fenytoine, hypericum,
 mitotaan, nevirapine, primidon, rifabutine, rifampicine;