A Randomized Study to Investigate the Effect of Intravenous Imatinib on the Amount of Oxygen in the Lungs and Blood of Adults With COVID-19 Needing Mechanical Ventilation and Supportive Care.

Study Overview
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Brief Summary
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The COVID-19 pandemic has led to an increase in the number of patients admitted to intensive care units (ICU) 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 prevents fluid leak in the lungs in inflammatory conditions, while leaving the immune response intact. Adding imatinib into the standard care package may, therefore, decrease mortality and reduce the duration of mechanical ventilation compared with standard care alone, in critically-ill patients with COVID-19. To help determine the impact of imatinib in these patients we present a randomised, double-blind, multi-centre, 2-arm, parallel-group, placebo-controlled clinical study of intravenous imatinib in 84 mechanically-ventilated, adult subjects with COVID-19-related ARDS. Study participants (patients who have consented into the study) will receive the study drug (imatinib or placebo) twice daily for a period of 10 days. The effect of the intervention will be tested by measuring the change from baseline in the Oxygen Saturation Index (OSI) at day 10. OSI is a non-invasive means of measuring oxygenation and is an independent predictor of mortality in patients with ARDS, serving thus as a relevant endpoint from which to assess the efficacy of imatinib. Other measurements will include regular blood tests as part of safety assessments. Time on ventilation and morbidity and mortality will be recorded as secondary outcome measures. Blood tests will also allow the investigation of the pharmacokinetic properties of imatinib, as well as biomarkers of inflammation.

Official Title
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A Randomized, Double-blind, Multicentre 2-arm, Parallel-group, Placebo-controlled Study to Investigate the Efficacy and Safety of Intravenous Imatinib Mesylate in Reducing the Severity of Hypoxemic Respiratory Failure in Patients With Critical COVID-19 Receiving Standard of Care.

Conditions
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Acute Respiratory Distress Syndrome, Covid19, COVID-19 Acute Respiratory Distress Syndrome, ARDS, Pulmonary Oedema

Intervention / Treatment
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* Drug: Imatinib Mesylate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged ≥18 years Women of childbearing potential must have a negative serum pregnancy test to confirm eligibility Provision of signed written informed consent from the patient or patient's legally acceptable representative SARS-CoV-2 infection confirmed by RT-PCR laboratory test (which may include results from a test that was performed prior to hospital admission if, in the opinion of the Investigator, it is relevant to ongoing COVID-19) Meet Berlin definition for moderate - severe ARDS Bilateral opacities - not fully explained by effusions, lobar/lung collapse, or nodules Respiratory failure not fully explained by cardiac failure or fluid overload. PaO2/FIO2 ≤200 mmHg with PEEP ≥5 cmH2O Patient requires intubation or is currently intubated and has been for ≤48 hours Exclusion Criteria: Persistent septic shock (>24 hours) 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 Major trauma in the past 5 days Presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the last year Pre-existing severe cardiopulmonary disease including, but not limited to, interstitial lung disease; severe COPD (GOLD Stage IV or FEV1<30% predicted); heart failure (estimated left ventricular ejection fraction < 40%); or a chronic lung condition requiring home oxygen treatment An underlying clinical condition that, in the opinion of the Investigator, would make it very unlikely for the patient to be successfully weaned from ventilation due to severe underlying diseases (e.g., severe malnutrition, severe neurological disease) Patients considered inappropriate for critical care (e.g., being considered for palliative care) Currently receiving extracorporeal membrane oxygenation (ECMO) Severe chronic liver disease with Child-Pugh score >12 (Appendix 1) White blood count <2.5 x 109/L; Hemoglobin <4.0 mmol/L (6.5g/dL); Platelets <50 x 109/L ALT or AST >10x upper limit of normal (ULN) or bilirubin >3x ULN Women who are pregnant or breast-feeding Use of drugs with strong CYP3A4 induction potential, such as carbamazepine, efavirenz, enzalutamide, phenobarbital, phenytoin, hypericum, mitotane, nevirapine, primidone, rifabutin and rifampicin Inability of the ICU staff to initiate administration of study treatment within 48 hours of intubation Enrolled in a concomitant clinical trial of an investigational medicinal product In the opinion of the investigator, progression to death is highly probable, irrespective of the provision of treatments

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous Imatinib Mesylate<br>Intravenous Imatinib Mesylate solution- 200mg as an 8mg/ml solution, administered twice daily (400mg total daily dose). Each dose administered in a 25ml solution over a two-hour infusion period. | Drug: Imatinib Mesylate<br>* An isotonic sterile solution of imatinib.<br>* Other names: Impentri;|
| Placebo Comparator: Intravenous Placebo<br>Intravenous Placebo matched solution- administered 25ml solution, twice daily over a two-hour infusion period | Drug: Placebo<br>* An isotonic sterile solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Oxygen Saturation Index (OSI) at Day 10 | Oxygen saturation is a calculation derived from [mean airway pressure × FiO2 × 100] / SpO2. | From Baseline to Day 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Oxygen Saturation Index (OSI) at Day 3 and Day 5 | Oxygen saturation measured by pulse oximetry | From Baseline to Day 3 and from baseline to Day 5 | 
| Mortality rate at Day 29 and Day 60 | Mortality at Day 29 and Day 60 | Day 29 and Day 60 | 
| Change from baseline in WHO 9-point ordinal scale for clinical improvement to Day 10 and Day 29 | The WHO Ordinal Scale for Clinical Improvement (0 to 8, where a higher value indicates worse outcome). It measures illness severity over time using the following categories: Uninfected, Ambulatory (no limitation of activities), Ambulatory (limitation of activities), Hospitalized (no O2 therapy), Hospitalized (O2 by nasal prongs or mask), Hospitalized (O2 by NIV or HFNO), Hospitalized (intubation and invasive mechanical ventilation), Hospitalized (ventilation and additional organ support [vasopressors, CVVH, ECMO]), Death. | The WHO ordinal scale will be recorded Days 1-10 and Day 29 | 
| Duration of mechanical ventilation (Days) to Day 29 and Day 60 | Number of days requiring to be on mechanical ventilation | To Day 29 and to Day 60 | 
| Duration of stay in ICU (Days) to Day 29 and Day 60 | Number of days within the ICU | To Day 29 and to Day 60 | 
| Time to first successful extubation (Hours) to Day 29 | Number of hours to extubation (removal of the endotracheal tube) | To Day 29 | 
| Number of days free of mechanical ventilation and survival (VFDsurv) at Day 29 and Day 60 | Amongst survivors, the number of days free from mechanical ventilation | At Day 29 and Day 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Respiratory Distress Syndrome, ARDS, Covid-19, Imatinib, Oxygen Saturation Index, OSI, Endothelial Dysfunction, Pulmonary Oedema, Protein Kinase Inhibitor