Nebulized Recombinant Tissue Plasminogen Activator (rt-PA) for Acute COVID-19-Induced Respiratory Failure: An Exploratory Proof-of-Concept Trial

Pratima Chowdary; Banwari Agarwal; Maria Rita Peralta; Sanjay Bhagani; Simon Lee; James Goldring; Marc Lipman; Emal Waqif; Mark Phillips; Helen Philippou; Jonathan H Foley; Nicola J Mutch; Robert A S Ariëns; Kathleen A Stringer; Federico Ricciardi; Marie Watissée; Derralynn Hughes; Amit Nathwani; Anne Riddell; David Patch; Jim Buckley; Mark De Neef; Rahul Dimber; Cecilia Diaz-Garcia; Honey Patel; Aarti Nandani; Upuli Dissanayake; Nick Chadwick; Ahmed A A M M Alkhatip; Peter Watkinson; Eamon Raith; Suveer Singh; Tony Wolff; Rajeev Jha; Simon E Brill; Ameet Bakhai; Alison Evans; Farhat Gilani; Keith Gomez

doi:10.3390/jcm12185848

Nebulized Recombinant Tissue Plasminogen Activator (rt-PA) for Acute COVID-19-Induced Respiratory Failure: An Exploratory Proof-of-Concept Trial

J Clin Med. 2023 Sep 8;12(18):5848. doi: 10.3390/jcm12185848.

Authors

Pratima Chowdary^{1

2}, Banwari Agarwal³, Maria Rita Peralta^{1

2}, Sanjay Bhagani⁴, Simon Lee⁴, James Goldring⁵, Marc Lipman^{5

6}, Emal Waqif¹, Mark Phillips^{1

2}, Helen Philippou⁷, Jonathan H Foley⁸, Nicola J Mutch⁹, Robert A S Ariëns⁷, Kathleen A Stringer^{10

11}, Federico Ricciardi¹², Marie Watissée¹³, Derralynn Hughes², Amit Nathwani^{1

2}, Anne Riddell^{1

14}, David Patch¹⁵, Jim Buckley³, Mark De Neef³, Rahul Dimber³, Cecilia Diaz-Garcia¹, Honey Patel¹, Aarti Nandani¹⁶, Upuli Dissanayake¹, Nick Chadwick¹, Ahmed A A M M Alkhatip^{17

18}, Peter Watkinson¹⁹, Eamon Raith^{20

21}, Suveer Singh^{22

23

24}, Tony Wolff³, Rajeev Jha³, Simon E Brill⁶, Ameet Bakhai^{3

25}, Alison Evans²⁶, Farhat Gilani²⁶, Keith Gomez^{1

2}

Affiliations

¹ Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK.
² Cancer Institute, University College London, London WC1E 6DD, UK.
³ Department of Intensive Care and Anaesthesia, Royal Free London NHS Foundation Trust, London NW3 2QG, UK.
⁴ Department of Infectious Diseases, Royal Free London NHS Foundation Trust, London NW3 2QG, UK.
⁵ Respiratory Medicine, Royal Free London NHS Foundation Trust, London NW1 2BU, UK.
⁶ UCL Respiratory, University College London, London WC1E 6JF, UK.
⁷ Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK.
⁸ Freeline Therapeutics, London SG1 2BP, UK.
⁹ Aberdeen Cardiovascular & Diabetes Centre, School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.
¹⁰ Department of Clinical Pharmacy, College of Pharmacy University of Michigan, Ann Arbor, MI 48109, USA.
¹¹ Division of Pulmonary and Critical Care Medicine, School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
¹² Department of Statistical Science, University College London, London WC1E 6BT, UK.
¹³ WStats Limited, Winchester SO23 8GH, UK.
¹⁴ Haemophilia & Thrombosis Laboratory (Health Services Laboratories), Royal Free Hospital, London WC1H 9AX, UK.
¹⁵ Department of Hepatology, Royal Free London NHS Foundation Trust, London NW3 2QG, UK.
¹⁶ Clinical Trials Pharmacy, Royal Free London NHS Foundation Trust, London NW3 2QG, UK.
¹⁷ Department of Anaesthesia, Birmingham Children's Hospital, Birmingham B4 6NH, UK.
¹⁸ Department of Anaesthesia, Faculty of Medicine, Beni-Suef University Hospital, Beni-Suef University, Beni-Suef 2721562, Egypt.
¹⁹ NIHR Biomedical Research Centre Oxford, Oxford University Hospitals NHS Trust, University of Oxford, Oxford OX3 9DU, UK.
²⁰ Bloomsbury Institute for Intensive Care Medicine, Department of Experimental and Translational Medicine, University College London, London WC1E 6JF, UK.
²¹ Discipline of Acute Care Medicine, School of Medicine, The University of Adelaide, Adelaide, SA 5005, Australia.
²² Department of Respiratory and Critical Care Medicine, Chelsea & Westminster Hospital, London SW10 9NH, UK.
²³ Department of Adult Intensive Care, Royal Brompton Hospital, London SW3 6NP, UK.
²⁴ Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK.
²⁵ Department of Cardiology, Royal Free London NHS Foundation Trust, London NW3 2PS, UK.
²⁶ University College London (UCL)/University College London Hospitals NHS Trust (UCLH) Joint Research Office, London WC1E 6BT, UK.

Abstract

Acute lung injury in COVID-19 results in diffuse alveolar damage with disruption of the alveolar-capillary barrier, coagulation activation, alveolar fibrin deposition and pulmonary capillary thrombi. Nebulized recombinant tissue plasminogen activator (rt-PA) has the potential to facilitate localized thrombolysis in the alveolar compartment and improve oxygenation. In this proof-of-concept safety study, adults with COVID-19-induced respiratory failure and a <300 mmHg 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, between 23 April-30 July 2020 and 21 January-19 February 2021, respectively. Matched historical controls (MHC; n = 18) were used in C1 to explore efficacy. Safety co-primary endpoints were treatment-related bleeds and <1.0-1.5 g/L fibrinogen reduction. A variable dosing strategy with clinical efficacy endpoint and minimal safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40-60 mg rt-PA daily 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 bleeds (one severe, three mild) in three patients were considered treatment related. There were no significant fibrinogen reductions. Greater improvements in mean P/F ratio from baseline to study end were 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 the P/F ratio occurred in NIRS patients (NIRS; 126 to 240 vs. IMV; 120 to 188) and fewer treatment days were required (NIRS; 7.86 vs. IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, with a trend towards improved oxygenation, particularly in the NIRS group. Randomized clinical trials are required to demonstrate the clinical effect significance and magnitude.

Keywords: COVID-19 pandemic; acute respiratory illness; critical care; fibrinolytics; inhaled medication; nebulization; recombinant tissue plasminogen activator; targeted therapy.

Abstract

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