TY - JOUR
T1 - Efficacy and safety of intravenous imatinib in COVID-19 ARDS
T2 - a randomized, double-blind, placebo-controlled clinical trial
AU - Atmowihardjo, Leila N.
AU - Schippers, Job R.
AU - Duijvelaar, Erik
AU - Bartelink, Imke H.
AU - Bet, Pierre M.
AU - Swart, Noortje E. L.
AU - van Rein, Nienke
AU - Purdy, Keith
AU - Cavalla, David
AU - McElroy, Andrew
AU - Fritchley, Sarah
AU - Vonk Noordegraaf, Anton
AU - Endeman, Henrik
AU - van Velzen, Patricia
AU - Koopmans, Matty
AU - Bogaard, Harm Jan
AU - Heunks, Leo
AU - Juffermans, Nicole
AU - Schultz, Marcus J.
AU - Tuinman, Pieter R.
AU - Bos, Lieuwe D. J.
AU - Aman, Jurjan
N1 - Funding Information: This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement number 101005142. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA. For more information, see http://www.imi.europa.eu . The funder of this trial had no role in the trial design, data collection, data interpretation or writing of the scientific report. Publisher Copyright: © 2023, The Author(s).
PY - 2023/12/1
Y1 - 2023/12/1
N2 - Purpose: A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed pulmonary capillary leak in preclinical studies and improved clinical outcomes in hospitalized COVID-19 patients. We investigated the effect of intravenous (IV) imatinib on pulmonary edema in COVID-19 ARDS. Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial. Invasively ventilated patients with moderate-to-severe COVID-19 ARDS were randomized to 200 mg IV imatinib or placebo twice daily for a maximum of seven days. The primary outcome was the change in extravascular lung water index (∆EVLWi) between days 1 and 4. Secondary outcomes included safety, duration of invasive ventilation, ventilator-free days (VFD) and 28-day mortality. Posthoc analyses were performed in previously identified biological subphenotypes. Results: 66 patients were randomized to imatinib (n = 33) or placebo (n = 33). There was no difference in ∆EVLWi between the groups (0.19 ml/kg, 95% CI − 3.16 to 2.77, p = 0.89). Imatinib treatment did not affect duration of invasive ventilation (p = 0.29), VFD (p = 0.29) or 28-day mortality (p = 0.79). IV imatinib was well-tolerated and appeared safe. In a subgroup of patients characterized by high IL-6, TNFR1 and SP-D levels (n = 20), imatinib significantly decreased EVLWi per treatment day (− 1.17 ml/kg, 95% CI − 1.87 to − 0.44). Conclusions: IV imatinib did not reduce pulmonary edema or improve clinical outcomes in invasively ventilated COVID-19 patients. While this trial does not support the use of imatinib in the general COVID-19 ARDS population, imatinib reduced pulmonary edema in a subgroup of patients, underscoring the potential value of predictive enrichment in ARDS trials. Trial registration NCT04794088 , registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23).
AB - Purpose: A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed pulmonary capillary leak in preclinical studies and improved clinical outcomes in hospitalized COVID-19 patients. We investigated the effect of intravenous (IV) imatinib on pulmonary edema in COVID-19 ARDS. Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial. Invasively ventilated patients with moderate-to-severe COVID-19 ARDS were randomized to 200 mg IV imatinib or placebo twice daily for a maximum of seven days. The primary outcome was the change in extravascular lung water index (∆EVLWi) between days 1 and 4. Secondary outcomes included safety, duration of invasive ventilation, ventilator-free days (VFD) and 28-day mortality. Posthoc analyses were performed in previously identified biological subphenotypes. Results: 66 patients were randomized to imatinib (n = 33) or placebo (n = 33). There was no difference in ∆EVLWi between the groups (0.19 ml/kg, 95% CI − 3.16 to 2.77, p = 0.89). Imatinib treatment did not affect duration of invasive ventilation (p = 0.29), VFD (p = 0.29) or 28-day mortality (p = 0.79). IV imatinib was well-tolerated and appeared safe. In a subgroup of patients characterized by high IL-6, TNFR1 and SP-D levels (n = 20), imatinib significantly decreased EVLWi per treatment day (− 1.17 ml/kg, 95% CI − 1.87 to − 0.44). Conclusions: IV imatinib did not reduce pulmonary edema or improve clinical outcomes in invasively ventilated COVID-19 patients. While this trial does not support the use of imatinib in the general COVID-19 ARDS population, imatinib reduced pulmonary edema in a subgroup of patients, underscoring the potential value of predictive enrichment in ARDS trials. Trial registration NCT04794088 , registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23).
KW - ARDS
KW - COVID-19
KW - Endothelial barrier dysfunction
KW - Imatinib
KW - Pulmonary edema
KW - Vascular permeability
UR - http://www.scopus.com/inward/record.url?scp=85161412002&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s13054-023-04516-4
DO - https://doi.org/10.1186/s13054-023-04516-4
M3 - Article
C2 - 37291677
SN - 1466-609X
VL - 27
SP - 226
JO - Critical care (London, England)
JF - Critical care (London, England)
IS - 1
M1 - 226
ER -