PB0045 - A pilot, open-label, phase II clinical trial of nebulised recombinant tissue-plasminogen activator in patients with COVID-19 acute respiratory distress syndrome: the PACA trial

Sunday, July 10, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

Pratima Chowdary, MD

Consultant Haematologist
Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London, United Kingdom
London, England, United Kingdom

Co-Author(s)

BA

Banwari Agarwal

Consultant at the Department of Critical Care, Royal Free Hospital,London
Department of Intensive care and Anaesthesia, Royal Free London NHS Foundation Trust, London, UK
London, England, United Kingdom
Sb

Sanjay bhagani

Consultant Physician/Hon.Associate Professor Department of Infectious Disease/HIV Medicine
Department of Infectious Diseases, Royal Free London NHS Foundation Trust, London, UK
London, England, United Kingdom
ML

Marc Lipman

Consultant Physician and Professor of Medicine
Respiratory Medicine, Royal Free London NHS Foundation Trust, London, UK and UCL Respiratory, University College London, London, UK
London, England, United Kingdom
KG

Keith Gomez, PhD MRCP FRCPath

Consultant Haematologist
Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, UK and Cancer Institute, University College London, London, UK
London, England, United Kingdom

Background: Alveolar fibrin deposition and pulmonary microthrombi are pathophysiological features of COVID-19-induced respiratory failure. Nebulised thrombolysis offers locally targeted therapy with potentially lower bleed risk than systemic administration.

Aims: To investigate the safety and potential for clinical efficacy of nebulised recombinant tissue plasminogen activator (rt-PA) for improving oxygenation in patients hospitalised with COVID-19 complicated by mild to severe acute respiratory distress syndrome (ARDS).

Methods: Patients hospitalised with severe COVID-19 and a PaO2/FiO2 (P/F) ratio of < 300 (units), requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received 40–60mg per day of rt-PA, dosed for ≤14 days in a phase II, open-label, single-centre pilot study. Efficacy was assessed via improved oxygenation. Safety was assessed by treatment-related serious adverse event bleeding and reduction of fibrinogen to < 1.0–1.5 g/L.

Results: Nine (Cohort 1 [C1]; 6/9 IMV, 3/9 NIRS) and 26 adults (Cohort 2 [C2]; 12/26 IMV, 14/26 NIRS) received nebulised rt-PA alongside standard of care. Matched historical controls (HC) (n=18) were used for comparison in C1. Mean P/F ratio increased in both C1 groups from baseline (BL) to end of study (EOS) (rt-PA; 154.4 to 298.8 vs. HC; 154.1 to 211.6); a linear mixed effect model confirmed higher P/F ratios in the rt-PA group. Among C2 groups, greater improvements in mean P/F ratio from BL to EOS were seen in the NIRS group (NIRS; 125.5 to 239.4 vs. IMV; 120.3 to 188.2). Four potentially treatment-related bleeds were reported; no clinically significant fibrinogen reductions were observed. Lower mortality was observed in the C1 rt-PA group (11.1%) vs. the HC group (55.6%) and in the C2 NIRS group (21.4%) vs. the IMV group (41.7%).

Conclusion(s): Nebulised rt-PA is well-tolerated, improves oxygenation in patients with COVID-19-related ARDS, and merits a randomised controlled trial to confirm efficacy and potentially identify a subgroup of interest.