Abstract
BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has led to a disruptive increase in the number of intensive care unit (ICU) admissions with acute respiratory distress syndrome (ARDS). ARDS is a severe, life-threatening medical condition characterized by widespread inflammation and vascular leak in the lungs. Although there is no proven therapy to reduce pulmonary vascular leak in ARDS, recent studies demonstrated that the tyrosine kinase inhibitor imatinib reinforces the endothelial barrier and prevents vascular leak in inflammatory conditions, while leaving the immune response intact.MethodsThis is a randomized, double-blind, parallel-group, placebo-controlled, multicenter clinical trial of intravenous (IV) imatinib mesylate in 90 mechanically ventilated subjects with COVID-19-induced ARDS. Subjects are 18 years or older, admitted to the ICU for mechanical ventilation, meeting the Berlin criteria for moderate-severe ARDS with a positive polymerase chain reaction test for SARS-CoV2. Participants will be randomized in a 1:1 ratio to either imatinib (as mesylate) 200 mg bis in die (b.i.d.) or placebo IV infusion for 7 days, or until ICU discharge or death. The primary study outcome is the change in Extravascular Lung Water Index (EVLWi) between day 1 and day 4. Secondary outcome parameters include changes in oxygenation and ventilation parameters, duration of invasive mechanical ventilation, number of ventilator-free days during the 28-day study period, length of ICU stay, and mortality during 28 days after randomization. Additional secondary parameters include safety, tolerability, and pharmacokinetics.DiscussionThe current study aims to investigate the efficacy and safety of IV imatinib in mechanically ventilated subjects with COVID-19-related ARDS. We hypothesize that imatinib decreases pulmonary edema, as measured by extravascular lung water using a PiCCO catheter. The reduction in pulmonary edema may reverse hypoxemic respiratory failure and hasten recovery. As pulmonary edema is an important contributor to ARDS, we further hypothesize that imatinib reduces disease severity, reflected by a reduction in 28-day mortality, duration of mechanical ventilation, and ICU length of stay.Trial statusProtocol version and date: V3.1, 16 April 2021. Recruitment started on 09 March 2021. Estimated recruitment period of approximately 40 weeks.Trial registrationClinicalTrials.govNCT04794088. Registered on 11 March 2021.
Highlights
Background and rationale {6a} Background of ARDS due to COVID-19 The coronavirus disease 2019 (COVID-19) pandemic has led to an unanticipated increase in the number of patients with acute respiratory distress syndrome (ARDS) admitted to the intensive care unit (ICU), contributing to high morbidity and mortality
As pulmonary edema is an important contributor to ARDS, we further hypothesize that imatinib reduces disease severity, reflected by a reduction in 28-day mortality, duration of mechanical ventilation, and ICU length of stay
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 electronic Case Report Form (eCRF), we propose not to report AEs in a standard fashion, except for the following events: pulmonary embolism, as detected on contrast-enhanced chest CT, not leading to circulatory or pulmonary instability, the occurrence of infections, requiring initiation of antibiotic therapy; nonlife-threatening infusion reactions, including but not limited to skin rash
Summary
Background and rationale {6a} Background of ARDS due to COVID-19 The coronavirus disease 2019 (COVID-19) pandemic has led to an unanticipated increase in the number of patients with acute respiratory distress syndrome (ARDS) admitted to the intensive care unit (ICU), contributing to high morbidity and mortality. In these severe cases, COVID-19 infection is characterized by damage to the alveolocapillary wall and extensive pulmonary capillary leakage. The coronavirus disease 2019 (COVID-19) pandemic has led to a disruptive increase in the number of intensive care unit (ICU) admissions with acute respiratory distress syndrome (ARDS). There is no proven therapy to reduce pulmonary vascular leak in ARDS, recent studies demonstrated that the tyrosine kinase inhibitor imatinib reinforces the endothelial barrier and prevents vascular leak in inflammatory conditions, while leaving the immune response intact
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