Nebulized recombinant tissue plasminogen activator (rt-PA) for acute COVID-19-induced severe respiratory failure: an exploratory proof of concept trial

Chowdary, P.; Agarwal, B.; Peralta, M.R.; Bhagani, S.; Lee, S.; Goldring, J.; Lipman, M.; Waqif, E.; Phillips, M.; Philippou, H.; Foley, J.H.; Mutch, N.J.; Ariëns, R.A.S.; Stringer, K.A.; Ricciardi, F.; Watissée, M.; Hughes, D.; Nathwani, A.; Riddell, A.; Patch, D.; Buckley, J.; De Neef, M.; Dimber, R.; Diaz-Garcia, C.; Patel, H.; Nandani, A.; Dissanayake, U.; Chadwick, N.; Alkhatip, A.A.A.M.M.; Watkinson, P.; Raith, E.; Singh, S.; Wolff, T.; Jha, R.; Brill, S.E.; Bakhai, A.; Evans, A.; Gilani, F.; Gomez, K. Nebulized Recombinant Tissue Plasminogen Activator (rt-PA) for Acute COVID-19-Induced Respiratory Failure: An Exploratory Proof-of-Concept Trial. J. Clin. Med. 2023, 12, 5848. Chowdary, P.; Agarwal, B.; Peralta, M.R.; Bhagani, S.; Lee, S.; Goldring, J.; Lipman, M.; Waqif, E.; Phillips, M.; Philippou, H.; Foley, J.H.; Mutch, N.J.; Ariëns, R.A.S.; Stringer, K.A.; Ricciardi, F.; Watissée, M.; Hughes, D.; Nathwani, A.; Riddell, A.; Patch, D.; Buckley, J.; De Neef, M.; Dimber, R.; Diaz-Garcia, C.; Patel, H.; Nandani, A.; Dissanayake, U.; Chadwick, N.; Alkhatip, A.A.A.M.M.; Watkinson, P.; Raith, E.; Singh, S.; Wolff, T.; Jha, R.; Brill, S.E.; Bakhai, A.; Evans, A.; Gilani, F.; Gomez, K. Nebulized Recombinant Tissue Plasminogen Activator (rt-PA) for Acute COVID-19-Induced Respiratory Failure: An Exploratory Proof-of-Concept Trial. J. Clin. Med. 2023, 12, 5848.

Abstract

Nebulized thrombolysis offers locally targeted therapy with potentially lower bleeding risk than systemic administration for coronavirus disease 2019 (COVID-19) respiratory failure. In a proof-of-concept safety study, adult patients with COVID-19-induced respiratory failure and a <300mmHg PaO2/FiO2 (P/F) ratio, requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care during the first two UK COVID-19 waves. Matched historical controls (MHC; n=18) were used in C1. Safety co-primary endpoints were treatment-related bleeds and fibrinogen reduction to <1.0–1.5 g/L. A dose escalation strategy for improved efficacy with the least safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40–60 mg rt-PA per day for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeding events (one severe and three mild) in three patients were considered treatment-related. No significant fibrinogen reductions were reported. Greater improvement in mean P/F ratio from baseline to end of study was observed in C1 compared with MHC [C1; 154 to 299 vs MHC; 154 to 212). In C2, there was no difference in the baseline P/F ratio of NIRS and IMV patients. However, a larger improvement in P/F ratio was observed in NIRS patients [NIRS; 126 to 240 vs IMV; 120 to 188) and they required fewer treatment days (NIRS; 7.86 vs IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, showing a trend of improved oxygenation and faster recovery in patients with acute COVID-19-induced respiratory failure requiring respiratory support; this effect was more pronounced in the NIRS group. Further investigation is required to study the potential of this novel treatment approach.

Keywords

Acute respiratory illness; critical care; recombinant tissue plasminogen activator; nebulization, fibrinolytics, COVID-19 pandemic, inhaled medication, targeted therapy

Subject

Medicine and Pharmacology, Pulmonary and Respiratory Medicine

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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