Acute Respiratory Distress Syndrome, ARDS, Covid19, COVID-19 Acute Respiratory Distress Syndrome, Pulmonary Oedema
Conditions
Keywords
Acute Respiratory Distress Syndrome, ARDS, Covid-19, Imatinib, Oxygen Saturation Index, OSI, Endothelial Dysfunction, Pulmonary Oedema, Protein Kinase Inhibitor
Brief summary
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.
Interventions
DRUGImatinib Mesylate
An isotonic sterile solution of imatinib.
DRUGPlacebo
An isotonic sterile solution
Sponsors
Exvastat Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female patients aged ≥18 years 2. Women of childbearing potential must have a negative serum pregnancy test to confirm eligibility 3. Provision of signed written informed consent from the patient or patient's legally acceptable representative 4. 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) 5. Meet Berlin definition for moderate - severe ARDS 1. Bilateral opacities - not fully explained by effusions, lobar/lung collapse, or nodules 2. Respiratory failure not fully explained by cardiac failure or fluid overload. 3. PaO2/FIO2 ≤200 mmHg with PEEP ≥5 cmH2O 6. Patient requires intubation or is currently intubated and has been for ≤48 hours
Exclusion criteria
1. 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 2. Major trauma in the past 5 days 3. Presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the last year 4. 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 5. 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) 6. Patients considered inappropriate for critical care (e.g., being considered for palliative care) 7. Currently receiving extracorporeal membrane oxygenation (ECMO) 8. Severe chronic liver disease with Child-Pugh score \>12 (Appendix 1) 9. White blood count \<2.5 x 109/L; Hemoglobin \<4.0 mmol/L (6.5g/dL); Platelets \<50 x 109/L 10. ALT or AST \>10x upper limit of normal (ULN) or bilirubin \>3x ULN 11. Women who are pregnant or breast-feeding 12. Use of drugs with strong CYP3A4 induction potential, such as carbamazepine, efavirenz, enzalutamide, phenobarbital, phenytoin, hypericum, mitotane, nevirapine, primidone, rifabutin and rifampicin 13. Inability of the ICU staff to initiate administration of study treatment within 48 hours of intubation 14. Enrolled in a concomitant clinical trial of an investigational medicinal product 15. In the opinion of the investigator, progression to death is highly probable, irrespective of the provision of treatments
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in Oxygen Saturation Index (OSI) at Day 10 | From Baseline to Day 10 | Oxygen saturation is a calculation derived from \[mean airway pressure × FiO2 × 100\] / SpO2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in WHO 9-point ordinal scale for clinical improvement to Day 10 and Day 29 | The WHO ordinal scale will be recorded Days 1-10 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. |
| Duration of stay in ICU (Days) to Day 29 and Day 60 | To Day 29 and to Day 60 | Number of days within the ICU |
| Time to first successful extubation (Hours) to Day 29 | To Day 29 | Number of hours to extubation (removal of the endotracheal tube) |
| Number of days free of mechanical ventilation and survival (VFDsurv) at Day 29 and Day 60 | At Day 29 and Day 60 | Amongst survivors, the number of days free from mechanical ventilation |
| Change from Baseline in Oxygen Saturation Index (OSI) at Day 3 and Day 5 | From Baseline to Day 3 and from baseline to Day 5 | Oxygen saturation measured by pulse oximetry |
| Mortality rate at Day 29 and Day 60 | Day 29 and Day 60 | Mortality at Day 29 and Day 60 |
| Duration of mechanical ventilation (Days) to Day 29 and Day 60 | To Day 29 and to Day 60 | Number of days requiring to be on mechanical ventilation |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic- Imatinib plasma concentration | 4 samples collected Day 1, and single samples collected Days 3 and 5 | Imatinib plasma concentration- Multivariate hierarchical analysis will be performed on various factors (age, sex, weight, height,appha-1-acid glycoprotein, haemoglobin, ALAT, CRP, eGFR, albumin, smoking, and concomitant drugs) to explore sources of variability in patient outcome. Significant predictors will be used as covariates to improve the performance of the PK model. |
| Safety- Type, frequency, severity, and relationship to study treatment of any AEs, SAEs or AEs leading to discontinuation of study treatment from Day 1 to Day 29 (final follow up visit) | Day 1 to Day 29 | Safety adverse events and serious adverse event collection |
| Incidence of related Treatment-Emergent Adverse Events- Tolerability | Day 1 to Day 29 | Tolerability |
Countries
India
Outcome results
None listed