Phase 1 trial of intrapleural LTI-01; single chain urokinase in complicated parapneumonic effusions or empyema.

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.

• Authors: Lutz Beckert, Ben Brockway, Graham Simpson, Anne Marie Southcott, Y C Gary Lee, Najib Rahman, Richard W Light, Steven Shoemaker, John Gillies, Andrey A Komissarov, Galina Florova, Timothy Ochran, William Bradley, Harrison Ndetan, Karan P Singh, Krishna Sarva, Steven Idell
• Journal: JCI insight (JCI Insight) Vol. 5 (04 18 2019) ISSN: 2379-3708 [Electronic] United States
• PMID: 30998508 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• fibrinolytic agent LTI-01
• Urokinase-Type Plasminogen Activator

Topics

• Adult
• Aged
• Aged, 80 and over
• Empyema, Pleural (drug therapy)
• Female
• Humans
• Injections, Intralesional
• Male
• Middle Aged
• Pleural Effusion (drug therapy)
• Thrombolytic Therapy (methods)
• Treatment Outcome
• Urokinase-Type Plasminogen Activator (administration & dosage, adverse effects)