The LTI-01-2001 Phase 2 Trial of Intrapleural LTI-01 in Patients with Infected, Non- Draining Pleural Effusions

Background: Single chain urokinase (LTI-01) intrapleural enzymatic therapy (IPET) was safe and promising in a phase 1 clinical trial to overcome failed drainage in patients with pleural infection. The LTI-01-2001 phase 2 trial was a randomized, double-blind, placebo-controlled, multi-center, dose-ranging study in hospitalized subjects with infected, non-draining pleural effusions. Methods: LTI-01, in doses of 400,000, 800,000 or 1.2 million Units, or placebo was administered intrapleurally once daily for up to 3 days. The primary efficacy endpoint was incidence of treatment failure within 7 days of starting study medication. Treatment failure was defined as requiring alternative pleural therapy irrespective of subsequent treatment. Pleural opacification was a secondary endpoint and was assessed by CT imaging of the change in opacified area expressed as a percentage of the ipsilateral hemithorax (relative change) or absolute change in pleural opacification volume expressed in liters. Results: 40/43 enrolled patients received LTI-01 or placebo due to constraints of the COVID-19 pandemic. There was no significant difference in incidence of treatment failure between the LTI-01 and placebo groups while two predetermined sensitivity analyses demonstrated trends of improved efficacy in the 400,000U group (P=0.052 and 0.147). The absolute (Liters; L) and relative change from baseline in opacity volume were -0.28L (p=.035) and -55.8% (p=0.064) versus placebo in the 800,000 U group, with significant reduction in absolute opacification found in the 400,000 and all LTI-01-treated groups combined (P<0.03, respectively). There were no safety signals of concern, nor were there any episodes of intrapleural or pulmonary bleeding in LTI-01-treated patients. Conclusions: No statistically significant difference in the incidence of treatment failure was seen, potentially related to low recruitment. Trends towards efficacy were observed in predetermined sensitivity analyses at the 400,000 dose of intrapleural LTI-01. Pleural opacification appeared most improved by the 800,000U intrapleural LTI-01. A larger phase 2b trial is required to confirm these results or determine the efficacy of LTI-01 in patients with organizing, nondraining, infected pleural effusions. Trial registration: ClinicalTrials.gov NCT04159831 . Registration date: November 12, 2019