Lutz Beckert1, Ben Brockway2, Graham Simpson3, Anne Marie Southcott4, Y C Gary Lee5, Najib Rahman6, Richard W Light7, Steven Shoemaker8, John Gillies9, Andrey A Komissarov10, Galina Florova10, Timothy Ochran11, William Bradley12, Harrison Ndetan13, Karan P Singh13, Krishna Sarva10, Steven Idell10. 1. University of Otago, Christchurch, New Zealand. 2. University of Otago Dunedin School of Medicine, Dunedin, New Zealand. 3. Cairns Hospital, Cairns, Queensland, Australia. 4. Western Health, Footscray, Victoria, Australia. 5. Sir Charles Gairdner Hospital, Perth, Western Australia, Australia. 6. Nuffield Department of Medicine, University of Oxford, and Oxford NIHR Biomedical Research Centre, Oxford, United Kingdom. 7. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. 8. Nicosof LLC, Erie, Colorado, USA. 9. Clinical Network Services (CNS), Auckland, New Zealand. 10. Departments of Cellular and Molecular Biology. 11. Innovation Initiative. 12. Department of Radiation Oncology, and. 13. Department of Epidemiology and Biostatistics, School of Community and Rural Health, The University of Texas Health Science Center at Tyler (UTHSCT), Tyler, Texas, USA.
Abstract
BACKGROUND: Current dosing of intrapleural fibrinolytic therapy (IPFT) in adults with complicated parapneumonic effusion (CPE) / empyema is empiric, as dose-escalation trials have not previously been conducted. We hypothesized that LTI-01 (scuPA), which is relatively resistant to PA inhibitor-1 (PAI-1), would be well-tolerated. METHODS: This was an open-label, dose-escalation trial of LTI-01 IPFT at 50,000-800,000 IU daily for up to 3 days in adults with loculated CPE/empyema and failed pleural drainage. The primary objective was to evaluate safety and tolerability, and secondary objectives included assessments of processing and bioactivity of scuPA in blood and pleural fluid (PF), and early efficacy. RESULTS: LTI-01 was well tolerated with no bleeding, treatment-emergent adverse events or surgical referrals (n=14 subjects). uPA antigen increased in PFs at 3 hours after LTI-01 (p<0.01) but not in plasma. PF saturated active PAI-1, generated PAI-1-resistant bioactive complexes, increased PA and fibrinolytic activities and D-dimers. There was no systemic fibrinogenolysis, nor increments in plasma D-dimer. Decreased pleural opacities occurred in all but one subject. Both subjects receiving 800,000 IU required two doses to relieve pleural sepsis, with two other subjects similarly responding at lower doses. CONCLUSION: LTI-01 IPFT was well-tolerated at these doses with no safety concerns. Bioactivity of LTI-01 IPFT was confirmed, limited to PFs where its processing simulated that previously reported in preclinical studies. Preliminary efficacy signals including reduction of pleural opacity were observed.
BACKGROUND: Current dosing of intrapleural fibrinolytic therapy (IPFT) in adults with complicated parapneumonic effusion (CPE) / empyema is empiric, as dose-escalation trials have not previously been conducted. We hypothesized that LTI-01 (scuPA), which is relatively resistant to PA inhibitor-1 (PAI-1), would be well-tolerated. METHODS: This was an open-label, dose-escalation trial of LTI-01 IPFT at 50,000-800,000 IU daily for up to 3 days in adults with loculated CPE/empyema and failed pleural drainage. The primary objective was to evaluate safety and tolerability, and secondary objectives included assessments of processing and bioactivity of scuPA in blood and pleural fluid (PF), and early efficacy. RESULTS: LTI-01 was well tolerated with no bleeding, treatment-emergent adverse events or surgical referrals (n=14 subjects). uPA antigen increased in PFs at 3 hours after LTI-01 (p<0.01) but not in plasma. PF saturated active PAI-1, generated PAI-1-resistant bioactive complexes, increased PA and fibrinolytic activities and D-dimers. There was no systemic fibrinogenolysis, nor increments in plasma D-dimer. Decreased pleural opacities occurred in all but one subject. Both subjects receiving 800,000 IU required two doses to relieve pleural sepsis, with two other subjects similarly responding at lower doses. CONCLUSION: LTI-01 IPFT was well-tolerated at these doses with no safety concerns. Bioactivity of LTI-01 IPFT was confirmed, limited to PFs where its processing simulated that previously reported in preclinical studies. Preliminary efficacy signals including reduction of pleural opacity were observed.
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