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

The LTI-01-2001 Phase 2 Trial of Intrapleural LTI-01 in Patients with Infected, Non- Draining Pleural Effusions | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The LTI-01-2001 Phase 2 Trial of Intrapleural LTI-01 in Patients with Infected, Non- Draining Pleural Effusions Carla Lamb, Jason Akulian, Ali Musani, Samira Shojaee, Alexander Chen, and 19 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9348224/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 13 You are reading this latest preprint version Abstract 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 Empyema single chain urokinase plasminogen activator fibrinolysis intrapleural enzymatic therapy complicated parapneumonic pleural effusions nondraining pleural effusions plasminogen activator inhibitor-1 Figures Figure 1 Figure 2 Figure 3 BACKGROUND Intrapleural organization with fibrinous loculations can impair pleural drainage and negatively impact outcomes of infectious pleural diseases such as empyema or complicated parapneumonic pleural effusions (CPE)[ 1 ]. For over seventy-five years, intrapleural enzymatic therapy (IET) has been used as an adjunct to antibiotics and chest tube drainage to clear loculated collections of inflammatory pleural fluid, expedite drainage and improve clinical outcomes[ 1 , 2 ].IET is now often used prior to surgical referral or in patients who are not surgical candidates, but treatment failure can occur in up to 25% of patients and IET dosing is empiric[ 3 , 4 ]. At present, the combination of tPA and DNase is most common form of IET, based on efficacy demonstrated in the MIST2 clinical trial[ 5 ]. Single chain urokinase (scuPA) is a proenzyme that exhibits Plasminogen Activator Inhibitor-1 (PAI-1) resistant properties that contributes to its ability to effectively and safely clear fibrinous pleural collections in rabbit models of pleural loculation and empyema[ 6 , 7 ]. With the support of a Science Moving TowArds Research Translation and Therapy (SMARTT) contract (HHSN268201100014C) from the NHLBI, the expression of scuPA in Chinese Hamster Ovarian (CHO) cells was improved and toxicology studies were done to support approval of a clinical trial testing program that was initiated by Lung Therapeutics Incorporated (LTI), which continued to optimize expression and stability of the scuPA drug product, called LTI-01. In a phase 1 clinical dose ranging clinical trial performed in Australia, LTI-01 proved to be safe in a phase 1 trial of patients with empyema/CPE and failed pleural drainage[ 8 ]. To our knowledge, this was the first dose ranging trial of IET in the field and hints of efficacy were observed. Here, we report the results of the phase 2a trial of intrapleural LTI-01 in patients with empyema/CPE and failed pleural drainage. This was a multicenter, double blind, randomized, placebo-controlled, multicenter, dose-ranging study in hospitalized subjects with infected, non-draining pleural effusions conducted in the US from September 2020 to March 2022 (Fig. 1 ). A range of clinical outcomes, including treatment failure or mortality and pleural opacification change were assessed to enable larger scale clinical trial testing of the ability of intrapleural LTI-01 to expedite drainage of pleural fluids and improve the clinical status of patients with infected, non-draining pleural effusions. A key objective prior to trial initiation was also to identify an effective dose(s) with a favorable benefit risk profile to enable Phase 2b or 3 dosing of LTI-01 administered intrapleurally in patients with infected, non-draining pleural effusions. METHODS Sex as a biologic variable. Both male and female subjects were included in this study, as shown in Table 1. The findings were anticipated to be relevant to each sex, as pleural infections and complications occur in both. Study Design. This was a phase 2a randomized, double-blind, placebo-controlled, multi-center, dose- ranging study conducted in hospitalized subjects at 18 sites in the US with infected, non-draining pleural effusions due to empyema/CPE. The trial was sponsored by Lung Therapeutics, Inc. (LTI) using company resources. The findings from the Phase 1 study supported further clinical development in the LTI-01-2001 and the trial design is illustrated (Figure 1). Planned trial enrollment and the dosing range are shown in Figure 1A and the trial flow chart is shown in Figure 1B. Monitoring for dose limiting toxicity (DLT) was done by the iDMC. LTI held the investigational IND for this trial, which was conducted between September of 2020 and July of 2022 with last update in March of 2023. The ClinicalTrials.gov registration number is NCT04159831. The authors designed or performed the trial, analyzed and archived the data, made the decision to submit the publication and vouch for the accuracy of the data and analyses. The study protocol is included in the Supplement to this article. Patient Eligibility, Inclusion and Exclusion Criteria. Eligible patients met all of the following inclusion criteria (Please refer to Supplement Study Protocol for details) : 1) Male or female ≥ 18 years of age 2) Clinical presentation compatible with CPE, empyema or other type of pleural infection 3) Pleural fluid requiring drainage as determined by chest ultrasonography, chest radiograph or chest CT which was either purulent, gram stain positive, culture positive, or pH < 7.2, glucose < 60 mg/dL (3.3 mmol/L). All patients had failure to adequately drain pleural fluid at least 3 hours after insertion of patent chest tube within the pleural space, as evidenced by 1 or more of the following criteria: 1) > 2 cm depth of fluid by ultrasound, chest radiograph or chest CT 2) < 80% drainage by chest radiograph compared with that obtained prior to chest tube. Exclusion related criteria included prior therapy with IET, fibrothorax, non-expandable lung preceding the present infectious episode and known malignant pleural effusions. Bleeding related exclusions included full anticoagulation, active bleeding or major trauma within 30 days. A full description of all exclusion criteria is provided in the Trial Protocol in the Supplement. Randomization, Monitoring and Outcomes. Randomization occurred using an Interactive Response Technology that notified unblinded pharmacy personnel of the dose assignment for specific study patients. Eligible patients were randomized in a 1:1:1:1 ratio to 1 of 4 dosing arms: placebo (intrapleural saline), 400,000 Units (U), 800,000 U or 1,200,000 U of LTI-01 with 25 - 40 patients per arm planned (100 – 160 patients total), in a double blinded fashion (investigators and patients). After the first 12 patients were randomized, subsequent patients were stratified for randomization based upon RAPID score to assess severity of the illness attributable to pleural infection.[9] Patients received once-daily doses of study medication (LTI-01 or placebo) administered intrapleurally on Days 1, 2 and 3. Patients were monitored daily until hospital discharge for continued, non-improving pleural infection and inadequate pleural fluid drainage. Patients who required alternative pleural therapy (tPA/DNase or surgical intervention) due to worsening or non-improving infected, non-draining pleural effusion, were considered treatment failures. Treatment failure in patients requiring alternative pleural therapy was defined as meeting protocol-specified criteria for surgical referral irrespective of subsequent treatment. In the event of treatment failure, patients were assessed by chest CT prior to surgery or initiation of alternative therapy; use of an alternative agent or surgical intervention. Treatment failures were communicated to the Sponsor Medical Monitor within 24 hours of referral to surgery or initiation of additional treatment. Documentation included confirmation of protocol-defined criteria for surgical referral or the rationale for surgical referral in its absence. It should also be noted that the treating clinicians were not restricted from treating subjects according to their own assessments to ensure that subjects were receiving safe and effective therapy in this placebo-controlled trial. Primary Endpoint. The primary efficacy endpoint was the Incidence of treatment failure or death within 7 days of starting study medication with treatment failure defined as requiring alternative pleural therapy and meeting protocol-specified criteria for surgical referral irrespective of subsequent treatment. Protocol-specified criteria for surgical referral included: Failure of complete pleural drainage as evidenced by > 2 cm pleural density assessed by chest computerized tomography (CT), chest radiograph or ultrasound. clinical AND evidence of ongoing systemic inflammatory response syndrome (SIRS) or pleural sepsis defined as ≥ 2 of: 1) Body temperature > 38°C or 90 beats per minute (BPM) for at least 2 observations in a 24-hour period 3) Respiratory rate > 20 breaths per minute or partial pressure of carbon dioxide in arterial blood (PaCO2) 12,000/mm3, 10% bands 5) Systolic blood pressure (SBP) < 100 or SBP drop ≥ 30 mmHg for at least 2 observations in a 24-hour period 6) C-reactive protein (CRP) < 50% reduced from study baseline. Two other prespecified primary analyses were also performed to assess the ability LTI-01 to affect the primary endpoint. The first was an analysis done by an iEAC assessment of treatment failure. The iEAC consisted of two academic interventional pulmonologists from the UK and one thoracic surgeon from Canada. In a second prespecified endpoint analysis, treatment failure was defined as requiring rescue therapy as determined by the treating physician. Secondary endpoints included absolute and relative change from baseline in pleural opacity volume assessed by chest CT at Day 4 or prior to initiation of alternative pleural therapy in the event of treatment failure. If a patient was considered a treatment failure on Day 3, approximately 24 hours after the second dose of study drug, the third dose of study drug was not administered, and a follow-up chest CT was performed on Day 3 before rescue therapy was initiated. Total number of hospitalization days from randomization to hospital discharge was assessed as well as mortality at 30 days. A complete description of the secondary efficacy endpoints is included in the study protocol included in the Supplement. Safety assessments included clinical bleeding and other adverse events (AE) with severity ratings based on National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Study medication. LTI-01 is a recombinant, human scuPA that has been cloned into CHO cells. It is formulated as a lyophilized powder designed for reconstitution with approximately 2.15 mL of sterile water for injection. The formulation is packaged in a 10 mL USP Type 1 glass vial (13 mm neck) finished with a chlorobutyl rubber stopper and sealed with an aluminum overseal with a flip-off cap. The reconstituted product is a sterile, single-use solution containing approximately 400,000 U in a formulation of 20 mM sodium citrate, 50 mM sodium chloride and 15 mg/mL mannitol, pH 4.5. Placebo is 0.9% sodium chloride for injection (USP Normal Saline). LTI-01 is designed to be stored at -20 ± 5 °C prior to use. Vials were reconstituted with approximately 2.15 mL sterile water, then brought to 6 ml with saline in a single syringe for thoracostomy tube administration followed by administration of 24 ml saline (30 ml total instillate), after which the tube was clamped for 3 hr., then reopened. Statistical Analyses. Point estimates and 95% confidence intervals (CI) of the Day 7 treatment failure rates were summarized for the LTI-01 dosing arms and placebo. Each LTI-01 dosing arm was compared to placebo using a two- sided test with significance level alpha of 0.05, to test the hypothesis of no difference in proportions for the primary endpoint for each of the LTI-01 dosing arms vs placebo. No adjustment for multiplicity was performed. Analyses of pleural opacification, indicative of pleural drainage, employed a two-sample t-test to test the hypothesis that the absolute change in pleural opacity in an LTI-01 group was not significantly different from that of placebo at an alpha of 0.05. The test was performed for each of the 4 groups. Additional tests were performed using one-way analysis of variance (ANOVA) to test that the absolute change in pleural opacity in an LTI-01 group is not different from that of placebo. To avoid any violations of normality assumptions, the data transformations were examined prior to analysis. The assumed response in the active dosing arms relative to placebo ranged from 15% to 25% in all considered models. Based on assumptions from the literature[5, 10, 11] and the Phase 1 study [8], a planned sample size of 25 to 40 patients per dosing arm was projected to provide 85% to 96% power for rejecting the null hypothesis of no difference in the primary endpoint between an LTI-01 dosing arm and placebo arm with an effect size ranging from 0.48 to 0.60 using a two-sided t-test with significance level alpha of 0.05. The same sample sizes were projected to support the identification of an effective dose(s) via MCP-Mod approach, with 90% power and 2.5% 1-sided significance level. RESULTS Patients. Enrollment was limited to a total of 43 patients, of whom 40 were dosed in one of 4 groups: 400,000 U, 800,000 U, 1,200,000 U, and placebo. The target enrollment in this study of 100-160 subjects (Figure 1A) was not achieved due in large part to research restrictions related to the COVID-19 pandemic. Subjects with infected non-draining pleural effusions received intrapleural administration by chest tube of study drug or placebo once daily for up to 3 days (please see Supplement, study protocol for details). Demographics of the study subjects are shown in Table 1. The primary analysis in Study LTI-01-2001 was conducted once all 40 enrolled subjects had completed their Day 30 assessments. Recruitment was put on hold, and safety was reviewed by the independent Data Monitoring Committee (iDMC) after 3 subjects had been entered into each dosing arm (12 subjects total) given that the 1,200,000 LTI-01 dose had not be studied previously. The iDMC determined that no tolerability issues had occurred. Dosing then proceeded in the four-dose groups as described In the Patient’s section above. Primary outcome: protocol defined treatment failure. There was no significant difference in incidence of treatment failure within 7 days of initiation of treatment between LTI-01 and placebo groups using the protocol definition of treatment failure (Table 2). When all patients treated with any dose of LTI-01 were considered, 11/29; 37.9% of patients experienced protocol-defined treatment failure while a comparable 4/11; 36% of placebo-treated patient had treatment failure. There were no deaths in any patients through 7 days of follow-up. The protocol defined treatment failure as requiring alternative pleural therapy and meeting protocol-specified criteria for surgical referral irrespective of subsequent treatment. These criteria included at least 2 signs of ongoing systemic inflammatory response syndrome (SIRS) or pleural sepsis and inadequate pleural fluid drainage. Examples of limitations concerning the protocol checklist are described in the Supplement. Pre-specified Sensitivity Analysis 1: independent Endpoint Assessment Committee (iEAC) assessment of treatment failure The iEAC evaluated blinded patient profiles that included brief demographic information, concomitant medications, pleural fluid characteristics, graphical representations of the SIRS/pleural sepsis criteria and had access to the baseline and follow-up CT scan images. The iEAC did not have access to site identification information, chest tube drainage information, or chest CT pleural opacity volume assessments made by a central reader. Examples of limitations of iEAC assessment in case examples are described in the Supplement. Based on this analysis, the 400,000 U LTI-01 group approached statistical significance versus placebo controls (1 treatment failure/10 subjects, OR 0.09, CI 0.01-1.02, P=0.052), while no other LTI-01 group demonstrated better outcomes by 7 days after initiation of LTI-01. Pre-specified Sensitivity Analysis 2: Treatment failure defined as requiring rescue therapy as determined by the treating physician In the second prespecified endpoint analysis, treatment failure was defined as needed for rescue therapy (other IET or surgery) as determined by the treating physician at 7 days, the 400,000 U and 800,000 U LTI-01 dose groups showed nonsignificant trends towards improved outcomes. The placebo incidence of treatment failure was 72.7%. That of the 400,000 U group was 40% (OR 0.26, 95% CI, 0.04-1.61, P=0.147). The 800,000 U incidence was 44.4% (OR 0.31, 95%, CI 0.05-2.02, p=0.221). A Forrest Plot of the primary outcome analyses of LTI-01 dosing groups versus placebo are illustrated in Figure 2. Incidence of Surgery at Day 30. Data collected for the endpoint captured actual surgery rather than referral for surgery (Table 3) through Day 30. The incidence of surgery at Day 30 rate was highest for placebo (45.5%) compared to the LTI-01 treated groups; LTI-01 400,000 U group: 30.0%, LTI-01 800,000 U group: 22.2%, LTI-01 1,200,000 U group: 10.0%, and LTI-01 group composite: 20.7%). Chi square=0.12 all LTI-01 groups combined versus placebo. Changes in pleural opacification. Change from baseline in pleural opacity volume at Day 4 was the key secondary efficacy endpoint since drainage of infected pleural fluid is a key element in controlling the source of the infection along with the administration of appropriate antibiotic therapy. The change in pleural opacity volume was assessed by chest CT by measuring the volumetric size (absolute size in liters) and relative percentage change in opacification of the infected pleural effusion at baseline and after treatment with study drug, indicating how much pleural fluid drained. Figure 2 shows that most subjects in all LTI-01 groups had a relative decrease from baseline in pleural opacity with a trend toward maximally decreased opacification in the 800,000 LTI-01 group. The outlier in the 800,000 U dose group had a 123% increase in pleural opacity volume presented with an esophageal perforation and pleural fluid characteristics suggesting leakage of swallowed oral secretions into the pleural space. For statistical comparisons, a ranked based ANCOVA was used as pre-specified in the trial statistical analysis plan since the normality assumption was not met. The 400,000 U and 800,000 U and overall LTI-01 dose groups showed a significant difference from placebo in absolute change of pleural opacity volume (p< 0.05) and similar trend with relative change from baseline pleural opacity volume (p-values 0.082 and 0.064, respectively), shown in Table 4. Relationship of changes in pleural opacification and clinical outcomes. Tables 5 and 6 illustrate that the relative change from baseline in pleural opacity volume can be divided into quartiles with Quartile 1 being the 25% of subjects with the largest decrease and Quartile 4 represents the 25% with the smallest decrease. Table 6 illustrates that there was a significant correlation between treatment failure and pleural opacity volume change (p-values <0.05), i.e. higher incidence of treatment failure is associated with smaller pleural opacity volume reduction. Based on these considerations, Quartile 4 subjects with the smallest relative decrease in pleural opacity volume had a 90% treatment failure rate in contrast to Quartile 1 subjects with the largest relative decrease in pleural opacity volume who had a 20% treatment failure rate. Based on this analysis, pleural opacity volume was indicative of the need for rescue therapy. Pleural fluid drainage. An exploratory endpoint in this trial was to assess the daily amount of fluid draining out of the chest tube. The mean cumulative fluid drainage was greater in the LTI-01 groups when at 1, 2 and 3d after initiation of LTI-01 IET compared to the placebo-treated patients but these trends did not achieve significance versus placebo (Table 7). Safety Analyses. Based on the analysis of treatment emergent adverse events (TEAEs) in the LTI-01 groups, there were no safety signals of concern (Table 8) and specifically no episodes of intrapleural or systemic bleeding events assessed as related to study drug (Table 9). Of note, there were no serious TEAEs related to study drug in any of the treatment groups. In the LTI-01 groups, 77.8% of TEAEs were unrelated to the agent. The most frequently occurring TEAEs (treatment emergent adverse events) were chest pain (4 subjects), constipation (4 subjects), and diarrhea (4 subjects) followed by insomnia (3 subjects). Five subjects died during the follow-up period up to 6 months after active dosing. No death was attributed to LTI-01 treatment. Additional details about each of these patients and of patients experiencing TEAEs is included in the Supplement. DISCUSSION This was, to our knowledge, the first-ever dose-ranging, randomized, double-blind, placebo-controlled, efficacy trial of a form of IET; LTI-01. The trial was performed at 18 US institutions in hospitalized subjects with infected, non-draining pleural effusions. The study was completed with last patient, last visit (Day 180) in July 2022. The intended enrollment was 25–40 subjects per arm (100–160 total with 3 LTI-01 doses and placebo). Enrollment was limited to 43 subjects due in large part to the COVID-19 pandemic, of which 40 subjects were dosed and included in the safety and efficacy analysis. While the use of a placebo group and study design may have contributed to this problem, we believe that resources and manpower allocations for the care of large numbers of COVID-19 patients were mainly responsible for limited enrollment. The analysis and interpretation of this study are thus constrained by relative paucity of enrollment and available data. There were no significant differences between any LTI-01 group and placebo-treated patients in the incidence treatment failure or death within 7 days using the protocol definitions. However, important findings including significant and nonsignificant efficacy signals of LTI-01 compared with placebo were found when considering the totality of the data. These findings also bear implications for the design of a future Phase 2b study in which better efficacy assessments can derive from larger treatment cohorts. The protocol defined failure as requiring alternative pleural therapy and meeting protocol-specified criteria for surgical referral irrespective of actual subsequent treatment. The criteria included at least 2 signs of ongoing systemic inflammatory response syndrome (SIRS) or pleural sepsis and inadequate pleural fluid drainage, which to our knowledge have not been used previously as part of a drug development program targeting regulatory approval. Because these criteria had not been assessed previously, subjects requiring rescue therapy were considered treatment failures that were discussed with the medical monitor and prespecified sensitivity analyses were performed, one by the iEAC and the other based on the treating physician’s assessment that alternative treatment (either other IET or surgery) was required. The iEAC assessment concluded that the 400,000 U LTI-01 dose resulted in less treatment failure than the placebo group, while the rescue treatment sensitivity analysis revealed nonsignificant trends towards reduced treatment failure in the 400,000 or 800,000 LTI-01 versus placebo groups (Please see outcome sensitivity analysis sections, Results). These findings support further testing in a larger phase 2b trial. The discordance between protocol checklist outcomes and iEAC sensitivity analysis outcomes triggered a reexamination of The Phase 2 protocol checklist criteria for defining treatment failure, which were found to have limitations. Situations in which subjects required surgery for evolving pleural fibrosis or trapped lung were not well captured by the protocol definition and in two placebo and one LTI-01 1.2 million U dose patients, rescue surgeries were performed despite meeting criteria as protocol treatment successes. These were, however, designated as treatment failures by iEAC and rescue therapy sensitivity analyses, accounting for some of the disparate conclusions. The iEAC assessments also had incomplete clinical information that appeared to have resulted in different conclusions, one in the 400,000 U and another in a patient in the 800,000 U LTI-01 group, which further contributed to the disparities. The sensitivity analyses are intriguing, clinically germane and supportive of clinical efficacy but do not obviate the protocol defined outcomes showing no difference in treatment failure. In a related outcome assessment, there was a decrement in the incidence in actual surgeries in the LTI-01 treatment versus placebo groups. Although the trends did not achieve statistical significance, more surgeries were done in the placebo versus LTI-01 groups. In the aggregate, we infer that analyses of treatment groups with larger numbers are required to reach conclusions about the efficacy of LTI-01 for non-draining empyema/CPE. In addition, protocol adjustments that better square the requirement for surgery of trapped lung or rescue IET will need to be incorporated into the study design of future trials. Changes in pleural opacification are important indicators of the efficacy of pleural drainage and there is clear evidence that they relate to the ability of IET to improve clinical outcomes. The findings of the MIST2 and MIST3 trials in particular strongly suggest that reduction of pleural opacification relates to clinically important outcome such as referral to surgery or length of hospital stay or quality of life[ 5 , 12 ]. In this trial, the absolute reduction in pleural opacification determined by noncontract chest CT imaging achieved statistical significance for both the 400,000U and 800,000U LTI-01 treated patients versus placebo (Table 7 ). The reduction of relative pleural opacification versus baseline approached statistical significance for the same groups, with the greatest relief or opacification observed in the 800,000 U treated patients (Table 7 and Fig. 3 ). There was no difference in pleural opacification in the 1,200,000 U LTI-01 group versus placebo. Differences in disease severity, suggested by the highest RAPID scores in this group or differences in aberrant intrapleural fibrin turnover or profibrogenic mediator expression may have been contributory. It is conceivable that all these factors could have influenced opacification readouts at the 1.200,000U dose of LTI-01 but this dose appears to have little predicate for future clinical trial testing. Based on the findings, a 400,000 or 800,000U dose of intrapleural LTI-01 may be considered for future clinical trial testing. While relative pleural opacification was extrapolated from chest X-rays in MIST2 and directly measured by chest CT in this study, the magnitude of change was greater in the LTI-01 800,000 group (-55.8%) versus placebo (-16.1%) (than that previously reported in MIST2 (tPA/DNase − 29.5, placebo − 17.2%). Caveats include measurement of medians of relative opacification in this trial versus means+/- standard deviations in MIST2, much larger patient groups of about 50 patients/group, 200 total in MIST2 and measurement of pleural opacification at day 7 in MIST2 [ 5 ] versus at day 4 in the present study. However, we believe that the data supports further evaluation of the effects of LTI-01 on pleural opacification in a future phase 2b trial. Pleural fluid evacuation increases after administration of tPA/DNase-based IET and occurs in conjunction with reduction of sequestered intrapleural fluid collections[ 5 , 13 ]. The same trends in thoracostomy tube drainage and relative pleural opacification were found by either CXR or CT imaging in a limited number of patients (n = 14) who received LTI-01 50,000-800,000 U LTI-01 daily over 3 days in our preceding phase 1 trial[ 8 ]. Trends of increased chest tube drainage were similarly observed in this study at each dose of intrapleural LTI-01 (Table 7 ) and we speculate that the relatively low numbers of patients evaluated contributed to the lack of statistically significant increments. Surprisingly, cumulative thoracostomy drainage was not increased in the 1.2 million U LTI-01 treatment group, consistent with the inability of this dose to approach significant improvement of absolute or relative pleural opacification. The relationship between reduced pleural opacification and other clinical outcomes in IET trials remains a point of interest. While we acknowledge that changes in pleural opacification are a surrogate outcome, there is evidence now that other clinical outcomes including hospital length of stay, referral or performance of surgery and extended mortality; 30 or more days beyond IET are related to improvement in pleural opacification.[ 5 , 12 ] We stratified the levels of pleural opacification by quartiles (Fig. 7A) after which we determined that the severity of opacification was significantly related to treatment failure (Fig. 7B). While the analysis is still limited by the relatively low numbers of patient responses evaluated (N = 40), it lends further support for the concept that changes in pleural opacification by IET relate to clinically meaningful outcomes. The safety assessments consolidate the favorable adverse event profile that we observed in the phase 1 LTI-01 dose ranging study.[ 8 ] Importantly, no bleeding events were again observed, attesting to the safety of administration of intrapleural LTI-01, including the highest 1,200,000U dose that exceeded this tested in phase 1. It is possible that the intrapleural processing of the proenzyme scuPA may offer advantages versus delivery of an active serine protease such as tPA[ 1 , 14 ]. While pleural fluid analyses can offer insight into individual responses to treatment[ 8 ], group trends could be obviated by the low numbers available in this study. It would be anticipated that plasminogen activator inhibitor-1; PAI-1, (the major inhibitor of pleural fluid plasminogen activator activity) levels and activity are most elevated in patients prone to treatment failure, as PAI-1 increases intrapleural septation, decreases pleural drainage and extends length of stay and mortality assessed over 30 days [ 1 , 15 ]. Single chain uPA generated by LTI-01 as a part of its intrapleural processing, it could induce mesothelial cell TGF-β and Tissue Factor (TF) expression. [ 1 ] Increased intrapleural TGF-β promotes intrapleural organization and fibrosis [ 16 ], as does TF [ 1 , 17 ]. Dedicated biochemical studies are comprehensive, labor intensive and outside the scope of this report, but we plan to conduct such analyses on pleural fluids from patients in this trial and share the findings in the future. CONCLUSIONS This trial offers several considerations that can potentially advance the field. This is the only dose-ranging phase 2 study of a form of IET of which we are aware and the first efficacy trial in which efficacy of LTI-01 was tested. This trial design enables the discovery of counter-intuitive responses to IET, as we observed with lack of reduction of pleural opacification in patients treated with 1,200,000 U LTI-01. Dosing of IET agents can be refined in a data-driven manner using this format, which addresses some of the empiricism that surrounds the current use of IET[ 4 ]. The favorable safety profile of LTI-01 IET originally identified in phase 1 testing was sustained in this trial and may offer advantages over tPA/DNase bleeding rates of about 4 percent.[ 18 ] The favorable reductions of pleural opacification and evidence of its relationship to reduced treatment failure support further evaluation of LTI-01 IET in a properly powered phase 2b study, which is feasible and now being planned. Abbreviations LTI-01- recombinant single chain urokinase plasminogen activator, IET- intrapleural enzymatic therapy, PAI-1- plasminogen activator inhibitor 1, TGF-β- transforming growth beta 1, TF- tissue factor, TEAE: treatment-emergent adverse event, National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE). Declarations Human Ethics and Consent to Participate. This study received Institutional Review Board approval from all participating institutions prior to study initiation. All subjects provided written informed consent prior to participation. This trial was conducted in accordance with ethical principles from the Declaration of Helsinki, and clinical research guidelines established by the United States Code of Federal Regulations (21 CFR Parts 50, 56, and 312) and the International Conference on Harmonisation (ICH) E6(R1) Guideline for Good Clinical Practice (GCP). Consent for publication. Not applicable. Availability of data and materials. All resource data generated or analyzed during this study are included in the supplementary data in an Excel file format. The trial protocol, supplemental patient data and individual author competing interest attestations are also available in the supplement that accompanies this report. Competing interests. Dr. Idell founded Lung Therapeutics, Inc. (LTI), which was acquired by Aileron, Inc, now called Rein Therapeutics, Inc. He has an equity position in Rein and received compensation as Chief Scientific Officer for LTI until about 2021. He remains a consultant for LTI, paid through about 2021. His declared conflicts of interest are managed through the UTHSCT and the UT System. He is an inventor on a relevant patent (USPTO 7332469) held by the UT Board of Regents and licensed to LTI. Dr Rahman has received consultancy fees from Lung Therapeutics, Inc. Dr. Windsor is President and Chief Executive Officer at Rein Therapeutics Inc. rebranded from Aileron, Inc., which acquired LTI and LTI before that, and is a director (since 2013) who receives equity and financial compensation for his roles at the company. Dr. Kurman has received grants from Biodesix, CSA Medical, Galvanize, Medtronic, Nuvaira, PrognomiQ, Pulmonx, and Veracyte and has served as a consultant for Ambu, Biodesix, Circulogene, Cook, Galvanize, Intuitive, Medtronic, Merit, Noah Medical, Pinnacle Biologics, PrognomiQ, Pulmonx, Steris, Veracyte, and Verona Pharma. Dr. Musani has served as a consultant for Intuitive. He has received research grants from Galvanize, Pinnacle, Veracyte, and Biodesix and has shares in EON. ICJME conflict of interests forms are available for each author in the supplemental material. Funding. Lung Therapeutics, Inc. Author contributions : CRL, JA, AM, SS, AC, JK, PJ, MS, DA, MW, SA. M A-H, KM, JP, LY, FK, FM and GC recruited patients, obtained informed consent, managed trial patients and assisted with the writing and review of the manuscript. BW helped develop the study and oversaw the sponsor’s financial and logistic commitments to the trial. NMR consulted on trial design, protocol development, review of the data and writing of the manuscript. CA and KPS performed statistical analyses and reviewed the manuscript. SS organized the trial design, protocol, trial data archive, reviewed the data related to the trial and contributed to writing of the manuscript. SI contributed to the trial design and trial data and its interpretation and wrote the manuscript. Acknowledgements. Not applicable. Authors’ information. Not applicable. Footnotes. Not applicable. References Komissarov AA, Rahman N, Lee YCG, Florova G, Shetty S, Idell R, Ikebe M, Das K, Tucker TA, Idell S: Fibrin turnover and pleural organization: bench to bedside. Am J Physiol Lung Cell Mol Physiol 2018, 314: L757–L768. Tillett WS, SHERRY S: THE EFFECT IN PATIENTS OF STREPTOCOCCAL FIBRINOLYSIN (STREPTOKINASE) AND STREPTOCOCCAL DESOXYRIBONUCLEASE ON FIBRINOUS, PURULENT, AND SANGUINOUS PLEURAL EXUDATIONS. J Clin Invest 1949, 28: 173–190. Siddiqui HA, Maginot ER, Moody TB, Henry R, Barrett CD: Pleural Space Diseases and Their Management: What is the Role of Intrapleural Fibrinolytic Therapy? Am Surg 2025, 91: 1036–1045. Idell S, Rahman NM: Intrapleural Fibrinolytic Therapy for Empyema and Pleural Loculation: Knowns and Unknowns. Ann Am Thorac Soc 2018, 15: 515–517. Rahman NM, Maskell NA, West A, Teoh R, Arnold A, Mackinlay C, Peckham D, Davies CW, Ali N, Kinnear W, et al: Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med 2011, 365: 518–526. Idell S, Mazar A, Cines D, Kuo A, Parry G, Gawlak S, Juarez J, Koenig K, Azghani A, Hadden W, et al: Single-Chain Urokinase Alone or Complexed to Its Receptor in Tetracycline-induced Pleuritis in Rabbits. Am J Respir Crit Care Med 2002, 166: 920–926. Komissarov AA, Florova G, Azghani AO, Buchanan A, Boren J, Allen T, Rahman NM, Koenig K, Chamiso M, Karandashova S, et al: Dose dependency of outcomes of intrapleural fibrinolytic therapy in new rabbit empyema models. Am J Physiol Lung Cell Mol Physiol 2016, 311: L389–399. Beckert L, Brockway B, Simpson G, Southcott AM, Lee YCG, Rahman N, Light RW, Shoemaker S, Gillies J, Komissarov AA, et al: Phase 1 trial of intrapleural LTI-01; single chain urokinase in complicated parapneumonic effusions or empyema. JCI Insight 2019, 5 . Rahman NM, Kahan BC, Miller RF, Gleeson FV, Nunn AJ, Maskell NA: A clinical score (RAPID) to identify those at risk for poor outcome at presentation in patients with pleural infection. Chest 2014, 145: 848–855. Diacon AH, Theron J, Schuurmans MM, Van de Wal BW, Bolliger CT: Intrapleural streptokinase for empyema and complicated parapneumonic effusions. Am J Respir Crit Care Med 2004, 170: 49–53. Hooper CE, Edey AJ, Wallis A, Clive AO, Morley A, White P, Medford AR, Harvey JE, Darby M, Zahan-Evans N, Maskell NA: Pleural irrigation trial (PIT): a randomised controlled trial of pleural irrigation with normal saline versus standard care in patients with pleural infection. Eur Respir J 2015, 46: 456–463. Bedawi EO, Stavroulias D, Hedley E, Blyth KG, Kirk A, De Fonseka D, Edwards JG, Internullo E, Corcoran JP, Marchbank A, et al: Early Video-assisted Thoracoscopic Surgery or Intrapleural Enzyme Therapy in Pleural Infection: A Feasibility Randomized Controlled Trial. The Third Multicenter Intrapleural Sepsis Trial-MIST-3. Am J Respir Crit Care Med 2023, 208: 1305–1315. Piccolo F, Pitman N, Bhatnagar R, Popowicz N, Smith NA, Brockway B, Nickels R, Burke AJ, Wong CA, McCartney R, et al: Intrapleural tissue plasminogen activator and deoxyribonuclease for pleural infection. An effective and safe alternative to surgery. Ann Am Thorac Soc 2014, 11: 1419–1425. Komissarov AA, Florova G, Azghani A, Karandashova S, Kurdowska AK, Idell S: Active alpha-macroglobulin is a reservoir for urokinase after fibrinolytic therapy in rabbits with tetracycline-induced pleural injury and in human pleural fluids. Am J Physiol Lung Cell Mol Physiol 2013, 305: L682–L692. Bedawi EO, Kanellakis NI, Corcoran JP, Zhao Y, Hassan M, Asciak R, Mercer RM, Sundaralingam A, Addala DN, Miller RF, et al: The Biological Role of Pleural Fluid PAI-1 and Sonographic Septations in Pleural Infection: Analysis of a Prospectively Collected Clinical Outcome Study. Am J Respir Crit Care Med 2022. Lee YC, Lane KB, Zoia O, Thompson PJ, Light RW, Blackwell TS: Transforming growth factor-beta induces collagen synthesis without inducing IL-8 production in mesothelial cells. Eur Respir J 2003, 22: 197–202. Mutsaers SE, Prele CM, Brody AR, Idell S: Pathogenesis of pleural fibrosis. Respirology 2004, 9: 428–440. Akulian J, Bedawi EO, Abbas H, Argento C, Arnold DT, Balwan A, Batra H, Uribe Becerra JP, Belanger A, Berger K, et al: Bleeding Risk With Combination Intrapleural Fibrinolytic and Enzyme Therapy in Pleural Infection: An International, Multicenter, Retrospective Cohort Study. Chest 2022, 162: 1384–1392. Tables Table 1: Subject Demographics and Baseline Characteristics ITT Population Category LTI-01 (400,000 U) N=10 n (%) LTI-01 (800,000 U) N=9 n (%) LTI-01 (1,200,000 U) N=10 n (%) LTI-01 Overall N=29 n (%) Placebo N=11 n (%) Age (Years) Median Min/Max 58.5 36/90 57.0 20/78 63.0 34/87 58.0 20/90 66.0 44/72 Sex (n, %) Male Female 6 (60) 4 (40) 5 (55.6) 4 (44.4) 6 (60) 4 (40) 17 (58.6) 12 (41.4) 8 (72.7) 3 (27.3) Race: Asian (%) Black (%) White (%) 1 (10) 1 (10) 8 (80) 0 2 (22.2) 6 (66.2) 1 (10) 2 (20) 7 (70) 2 (6.9) 5 (17.2) 21 (72.4) 0 1(9.1) 10 (90.9) Weight Median Min/Max 87.7 34.5/131.7 68.8 43.5/101.4 89.3 52.1/137.0 79.3 34.5/137.0 78.0 47.72/113.3 RAPID: Low Risk; 0-2 (%) Moderate Risk; 3-4 High Risk; 5-7 5 (50) 5 (50) 0 4 (44.4) 5 (55.6) 0 3 (30) 4 (40) 3 (30) 12 (41.4) 14 (48.3) 3 (10.3) 4 (36.4) 6 (54.5) 1 (9.1) Legend. One patient in the 800,000U group was listed as “Other” race. RAPID: Scoring system to predict outcomes after pleural infection (9). ITT: Intent to Treat. Table 2: Primary Efficacy Analysis: Incidence of Treatment Failure (Protocol Definition) Within 7 Days of Treatment. Treatment Failure LTI-01 (400,000 U) N=10 LTI-01 (800,000 U) N=9 LTI-01 ( 1,200,000 U) N=10 All LTI-01 N=29 Placebo N=11 Yes, n (%) 3 (30%) 3 (33.3%) 5 (50%) 11 (37.9%) 4 (36%) No, n (%) 7 (70%) 6 (66.7%) 5 (50%) 18 (62.1%) 7 (63%) Odds Ratio (OR) 0.77 0.91 1.57 1.04 95% CI (0.12, 4.84) (0.14, 5.83) (0.26, 9.51) (0.24, 4.44) P-value 0.782 0.917 0.625 0.958 Legend. CI = confidence interval Table 3. Secondary Efficacy Analysis: Logistic Regression of Incidence of Surgery at Day 30 Response LTI-01 (400,000 U) N=10 LTI-01 (800,000 U) N=9 LTI-01 (1,200,000 U) N=10 All LTI-01 N=29 Placebo N=11 Incidence of Referral to Surgery at Day 30, n (%) 3 (30.0) 2 (22.2) 1 (10.0) 6 (20.7) 5 (45.5) Odds Ratio 0.51 0.34 0.14 0.32 95% CI (0.08, 3.08) (0.05, 2.43) (0.01, 1.59) (0.07, 1.41) p-value 0.459 0.280 0.113 0.131 Legend. Abbreviations: CI = confidence interval; n = Number of patients with non-missing data within the specific category, N = Number of patients; Population; RAPID = composite clinical mortality risk score consisting of renal, age, purulence, infection source, and dietary factors Percentages were based on N. The logistic regression was performed with referral to surgery as the response variable, dose group, along with the RAPID score at randomization as the covariate. Table 4: Absolute and Relative Change from Baseline of Pleural Opacity Volume Statistics LTI-01 (400,000 U) N=10 LTI-01 (800,000 U) N=9 LTI-01 (1,200,000 U) N=10 LTI-01 Overall N=29 Placebo N=11 Absolute Change from Baseline (L) n 10 9 10 29 11 Median -0.255 -0.280 -0.140 -0.250 -0.100 p-value 0.027 0.035 0.311 0.026 Relative Change from Baseline (%) n 10 9 10 29 11 Median -33.84 -55.83 -23.04 -31.91 -16.05 p-value 0.082 0.064 0.466 0.070 Table 5: Quartiles for Relative Change from Baseline in Pleural Opacity Volume Quartile Relative change N 1 -49.9% to -27.8% to -12.0% 10 Table 6: Post hoc Analysis: Quartiles of Relative Change from Baseline in Pleural Opacity Volume and Count of Treatment Failure Quartiles P-value - Fisher Exact Test P-value- Cochran- Armitage Trend Test Q1 Q2 Q3 Q4 Count of Treatment Failure Yes 2 5 6 9 0.02 0.002 % Within Relative Quartiles 20% 50% 60% 90% Count of Treatment Failure No 8 5 4 1 % Within Relative Quartiles 80% 50% 40% 10% Total Count 10 10 10 10 Table 7: Analysis of Cumulative Pleural Fluid Drainage Via Thoracostomy Tube Timepoint Statistics LTI-01 (400,000 U) N=10 LTI-01 (800,000 U) N=9 LTI-01 (1,200,000 U) N=10 LTI-01 Overall N=29 Placebo N=11 24-hours post first dose (Day 2) n 10 9 10 29 11 LS Mean (SE) 544.7 (122.1) 577.2 (128.7) 483.0 (122.1) 533.5 (70.1) 353.7 (116.4) 95% CI (297.1 , 792.3) (316.2 , 838.2) (235.4 , 730.6) (391.7 , 675.4) (117.6 , 589.8) LS Mean Difference (SE) 191.0 (168.7) 223.5 (173.5) 129.3 (168.7) 179.8 (133.6) 95% CI (-151.2 , 533.1) (-128.5 , 575.5) ( -212.9 , 471.4) (-90.7 , 450.3) p-value 0.27 0.21 0.45 0.19 24-hours post second dose (Day 3) n 9 9 10 28 11 LS Mean (SE) 863.0 (172.6) 878.9 (172.6) 776.1 (163.7) 837.1 (95.5) 592.4 (156.1) 95% CI (512.6 , 1213.4) (528.5 , 1229.3) (443.7 , 1108.5) (643. 6 , 1030.5) (275.4 , 909.3) LS Mean Difference (SE) 270.6 (232.7) 286.5 (232.7) 183.7 (226.3) 244.7 (179.8) 95% CI ( -201.9 , 743.1) ( -186.0 , 759.0) ( -275.6 , 643.1) ( -119.5 , 609.0) p-value 0.25 0.23 0.42 0.18 24-hours post third dose (Day 4) n 8 9 9 26 11 LS Mean (SE) 939.6 (224.8) 1125.0 (211.9) 1142.0 (211.9) 1073.8 (122.0) 766.5 (191.7) 95% CI (482.3 , 1397.0) (693.8 , 1556.2) (710.8 , 1573.2) (826.1 , 1321.6) (376.4 , 1156.5) LS Mean Difference (SE) 173.2 (295.4) 358.5 (285.8) 375.5 (285.8) 307.4 (223.8) 95% CI ( -427.9 , 774.3) (-222.9 , 939.0) ( -205.9 , 957.0) (-147.0 , 761.7) p-value 0.56 0.22 0.20 0.18 Legend. CI: Confidence interval. LS Mean: Least-Squares mean values. Differences in LTI-01 treatment groups versus placebo controls are represented. Table 8: Summary of Treatment Emergent Adverse Events (TEAE)s) Category LTI-01 (400,000 U) N=10 n (%) LTI-01 (800,000 U) N=9 n (%) LTI-01 (1,200,000 U) N=10 n (%) LTI-01 Overall N=29 n (%) Placebo N=11 n (%) Overall N=40 n (%) Number of Subjects with TEAE 5 (50.0) 7 (77.8) 6 (60.0) 18 (62.1) 8 (72.7) 26 (65.0) Number of Subjects with Serious TEAE 1 (20.0) 0 1 (16.7) 2 (11.1) 1 (12.5) 3 (11.5) Number of Subjects with Treatment Related TEAE 1 (20.0) 2 (28.6) 1 (16.7) 4 (22.2) 0 4 (15.4) Number of Subjects with Serious Treatment Related TEAE 0 0 0 0 0 0 Number of Subjects with TEAE Leading to Study Drug Discontinuation 1 (20.0) 0 1 (16.7) 2 (11.1) 0 2 (7.7) Severity/CTCAE Grade Grade 1 (Mild) 2 (40.0) 3 (42.9) 2 (33.3) 7 (38.9) 7 (87.5) 14 (53.8) Grade 2 (Moderate) 0 3 (42.9) 0 3 (16.7) 0 3 (11.5) Grade 3 (Severe) 2 (40.0) 1 (14.3) 3 (50.0) 6 (33.3) 1 (12.5) 7 (26.9) Grade 4 (Life threatening) 0 0 0 0 0 0 Grade 5 (Death) 1 (20.0) 0 1 (16.7) 2 (11.1) 0 2 (7.7) Relationship to Study Drug Related 1 (20.0) 2 (28.6) 1 (16.7) 4 (22.2) 0 4 (15.4) Not Related 4 (80.0) 5 (71.4) 5 (83.3) 14 (77.8) 8 (100) 22 (84.6) Legend. TEAE: treatment-emergent adverse event, National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE). Table 9: TEAEs Occurring in >1 Subject in LTI-01 and Placebo Groups Preferred Term LTI-01 (400,000 U) N=10 n (%) LTI-01 (800,000 U) N=9 n (%) LTI-01 (1,200,000 U) N=10 n (%) LTI-01 Overall N=29 n (%) Placebo N=11 n (%) Overall N=40 n (%) Number of Subjects with at Least One TEAE 1 5 (50.0) 7 (77.8) 6 (60.0) 18 (62.1) 8 (72.7) 26 (65.0) Chest pain 0 2 (28.6) 2 (33.3) 4 (22.2) 0 4 (15.4) Constipation 3 (60.0) 1 (14.3) 0 4 (22.2) 0 4 (15.4) Diarrhea 1 (20.0) 2 (28.6) 0 3 (16.7) 1 (12.5) 4 (15.4) Insomnia 0 1 (14.3) 2 (33.3) 3 (16.7) 0 3 (11.5) Blood creatinine increased 1 (20.0) 0 1 (16.7) 2 (11.1) 0 2 (7.7) Dyspnea 1 (20.0) 0 1 (16.7) 2 (11.1) 0 2 (7.7) Hypocalcemia 2 (40.0) 0 0 2 (11.1) 0 2 (7.7) Medical device site pain 1 (20.0) 1 (14.3) 0 2 (11.1) 0 2 (7.7) Nausea 1 (20.0) 1 (14.3) 0 2 (11.1) 1 (12.5) 3 (11.5) Pleural effusion 0 1 (14.3) 1 (16.7) 2 (11.1) 0 2 (7.7) Pyrexia 1 (20.0) 0 1 (16.7) 2 (11.1) 0 2 (7.7) Thrombosis 0 2 (28.6) 0 2 (11.1) 0 2 (7.7) Legend. Percentages are based on number of subjects with TEAEs. Additional Declarations Competing interest reported. Competing interests. Dr. Idell founded Lung Therapeutics, Inc. (LTI), which was acquired by Aileron, Inc, now called Rein Therapeutics, Inc. He has an equity position in Rein and received compensation as Chief Scientific Officer for LTI until about 2021. He remains a consultant for LTI, paid through about 2021. His declared conflicts of interest are managed through the UTHSCT and the UT System. He is an inventor on a relevant patent (USPTO 7332469) held by the UT Board of Regents and licensed to LTI. Dr Rahman has received consultancy fees from Lung Therapeutics, Inc. Dr. Windsor is President and Chief Executive Officer at Rein Therapeutics Inc. rebranded from Aileron, Inc., which acquired LTI and LTI before that, and is a director (since 2013) who receives equity and financial compensation for his roles at the company. Dr. Kurman has received grants from Biodesix, CSA Medical, Galvanize, Medtronic, Nuvaira, PrognomiQ, Pulmonx, and Veracyte and has served as a consultant for Ambu, Biodesix, Circulogene, Cook, Galvanize, Intuitive, Medtronic, Merit, Noah Medical, Pinnacle Biologics, PrognomiQ, Pulmonx, Steris, Veracyte, and Verona Pharma. Dr. Musani has served as a consultant for Intuitive. He has received research grants from Galvanize, Pinnacle, Veracyte, and Biodesix and has shares in EON. ICJME conflict of interests forms are available for each author in the supplemental material. Supplementary Files JCIPaperShoemakerIdelCRAXLS.xls Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 14 May, 2026 Reviews received at journal 13 May, 2026 Reviews received at journal 11 May, 2026 Reviews received at journal 04 May, 2026 Reviews received at journal 29 Apr, 2026 Reviewers agreed at journal 21 Apr, 2026 Reviewers agreed at journal 19 Apr, 2026 Reviewers agreed at journal 14 Apr, 2026 Reviewers agreed at journal 14 Apr, 2026 Reviewers invited by journal 14 Apr, 2026 Editor assigned by journal 09 Apr, 2026 Submission checks completed at journal 09 Apr, 2026 First submitted to journal 07 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9348224","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":620590948,"identity":"bdab5379-e54f-43eb-a42b-9b5ae72cd2d5","order_by":0,"name":"Carla Lamb","email":"","orcid":"","institution":"Lahey Hospital and Medical Center, Pulmonary and Critical Care Medicine,","correspondingAuthor":false,"prefix":"","firstName":"Carla","middleName":"","lastName":"Lamb","suffix":""},{"id":620590949,"identity":"926bb239-8441-4f8b-89fb-b26cca9bcbe5","order_by":1,"name":"Jason Akulian","email":"","orcid":"","institution":"University of North Carolina Division of Pulmonary Diseases and Critical Care Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jason","middleName":"","lastName":"Akulian","suffix":""},{"id":620590950,"identity":"e5cdfb82-dcaa-4d5e-9e2f-78835bd412e1","order_by":2,"name":"Ali Musani","email":"","orcid":"","institution":"3Pulmonary and Sleep Medicine, Lenox Hill Hospital, Donald and Barbara Zucker School of Medicine at Hofstra University","correspondingAuthor":false,"prefix":"","firstName":"Ali","middleName":"","lastName":"Musani","suffix":""},{"id":620590951,"identity":"1e32d2f4-29b6-4179-9d82-80d97e180316","order_by":3,"name":"Samira Shojaee","email":"","orcid":"","institution":"Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Samira","middleName":"","lastName":"Shojaee","suffix":""},{"id":620590952,"identity":"e3330a2d-0325-4f2f-b9b6-74de501d4fa0","order_by":4,"name":"Alexander Chen","email":"","orcid":"","institution":"Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Chen","suffix":""},{"id":620590953,"identity":"9a329e4e-81e6-44c4-8fc3-fe8cc52f643e","order_by":5,"name":"Jonathan Kurman","email":"","orcid":"","institution":"Division of Pulmonary \u0026 Critical Care, Medical College of Wisconsin","correspondingAuthor":false,"prefix":"","firstName":"Jonathan","middleName":"","lastName":"Kurman","suffix":""},{"id":620590956,"identity":"5a08e343-9dc8-47f8-aa85-27fd8c6f6632","order_by":6,"name":"Pushan Jani","email":"","orcid":"","institution":"Interventional Pulmonology, UT Houston and Memorial Hermann-Texas Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Pushan","middleName":"","lastName":"Jani","suffix":""},{"id":620590957,"identity":"a2683c3f-eb97-4ba4-8821-556a9f6e99c8","order_by":7,"name":"Michal Senitko","email":"","orcid":"","institution":"Division of Pulmonary, Critical Care and Sleep Medicine, University of Mississippi Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Michal","middleName":"","lastName":"Senitko","suffix":""},{"id":620590958,"identity":"3c4c0860-33f6-460d-9e9c-80c750177efe","order_by":8,"name":"Danish Ahmad","email":"","orcid":"","institution":"Interventional Pulmonology, Division of Pulmonary, Sleep and Critical Care Medicine, Fox Chase Cancer Center Lewis Katz School of Medicine at Temple University","correspondingAuthor":false,"prefix":"","firstName":"Danish","middleName":"","lastName":"Ahmad","suffix":""},{"id":620590959,"identity":"fbed03dd-27e0-4392-8265-6be5f379ecfd","order_by":9,"name":"Momen Wahidi","email":"","orcid":"","institution":"Division of Pulmonary and Critical Care, Northwestern University Feinberg School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Momen","middleName":"","lastName":"Wahidi","suffix":""},{"id":620590960,"identity":"b90f5c4b-6526-45ab-a2e8-712c9f783429","order_by":10,"name":"Sikandar Ansari","email":"","orcid":"","institution":"Intermountain Health LDS Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sikandar","middleName":"","lastName":"Ansari","suffix":""},{"id":620590961,"identity":"c6a00f31-7db6-4b3b-aa9b-59fac098f016","order_by":11,"name":"Muhanned Abu-Hijleh","email":"","orcid":"","institution":"Division of Pulmonary and Critical Care Medicine, Interventional Pulmonology, UT Southwestern Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Muhanned","middleName":"","lastName":"Abu-Hijleh","suffix":""},{"id":620590962,"identity":"3ca1af3d-0988-49a0-90d9-f076cabad6b8","order_by":12,"name":"Kevin Ma","email":"","orcid":"","institution":"Pulmonary, Allergy and Critical Care, Perelman School of Medicine, The University of Pennsylvania","correspondingAuthor":false,"prefix":"","firstName":"Kevin","middleName":"","lastName":"Ma","suffix":""},{"id":620590965,"identity":"f83e736e-6451-4703-ac7b-2357348acb74","order_by":13,"name":"Jonathan Puchalski","email":"","orcid":"","institution":"Department of Pulmonology, Physicians Alliance of Connecticut (PACT),","correspondingAuthor":false,"prefix":"","firstName":"Jonathan","middleName":"","lastName":"Puchalski","suffix":""},{"id":620590966,"identity":"30438be8-339d-4e98-8166-c71a72dda260","order_by":14,"name":"Lonny Yarmus","email":"","orcid":"","institution":"Interventional Pulmonology, the Johns Hopkins University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Lonny","middleName":"","lastName":"Yarmus","suffix":""},{"id":620590967,"identity":"e00a871b-f3ae-4849-80b6-5f8a7fc46db8","order_by":15,"name":"Fayez Kheir","email":"","orcid":"","institution":"Pulmonary and Critical Care Medicine, Massachusetts General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fayez","middleName":"","lastName":"Kheir","suffix":""},{"id":620590968,"identity":"e76e4d98-b315-4276-afe0-d5bc1e40ffe0","order_by":16,"name":"Fabien Maldonado","email":"","orcid":"","institution":"Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University","correspondingAuthor":false,"prefix":"","firstName":"Fabien","middleName":"","lastName":"Maldonado","suffix":""},{"id":620590969,"identity":"4d56bd2f-e5ac-46fb-bc5b-1b90fef87834","order_by":17,"name":"George Cheng","email":"","orcid":"","institution":"Interventional Pulmonology, The University of California San Diego","correspondingAuthor":false,"prefix":"","firstName":"George","middleName":"","lastName":"Cheng","suffix":""},{"id":620590970,"identity":"13d84ec5-d2c1-4884-828a-19adbe0cc7c4","order_by":18,"name":"Christian Alvarado","email":"","orcid":"","institution":"Department of Epidemiology and Biostatistics, School of Medicine, The University of Texas at Tyler","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Alvarado","suffix":""},{"id":620590971,"identity":"53bd31d3-acff-4593-a4c8-c9370461f728","order_by":19,"name":"Karan Singh","email":"","orcid":"","institution":"Department of Epidemiology and Biostatistics, School of Medicine, The University of Texas at Tyler","correspondingAuthor":false,"prefix":"","firstName":"Karan","middleName":"","lastName":"Singh","suffix":""},{"id":620590972,"identity":"825110d5-0e2f-45d3-9363-70e8b5197d28","order_by":20,"name":"Brian Windsor","email":"","orcid":"","institution":"Rein Therapeutics, Inc.","correspondingAuthor":false,"prefix":"","firstName":"Brian","middleName":"","lastName":"Windsor","suffix":""},{"id":620590973,"identity":"85b6288d-3f28-419b-8490-772e5306bd03","order_by":21,"name":"Najib Rahman","email":"","orcid":"","institution":"Rein Therapeutics, Inc.","correspondingAuthor":false,"prefix":"","firstName":"Najib","middleName":"","lastName":"Rahman","suffix":""},{"id":620590974,"identity":"91f852b8-3d4f-49a6-a5f0-824a0b218ded","order_by":22,"name":"Steven Shoemaker","email":"","orcid":"","institution":"Nicosof LLC","correspondingAuthor":false,"prefix":"","firstName":"Steven","middleName":"","lastName":"Shoemaker","suffix":""},{"id":620590975,"identity":"ab6a2ffa-31ef-40f4-9701-9b963096dea3","order_by":23,"name":"Steven Idell","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8UlEQVRIiWNgGAWjYBADHoYDzI0HPjAwJEC5eAAbXAtjw8EZDAYJYBFitDCAtBzmIUaL/PzmYxIfdzDI8B1vbDhs2/Ynj39+A+ODt224tRgcY0uTnHmGgUfyzMGGw7ltBsUSxxiYDefi08LGY2zM28bAY3AjEawlcQMbA5s0Lx4t8m38n43/grTcf9hw2BKihf03Pi0Mx3gYHzOCbQF6nxFqCzM+LQbH0gwf9rZJAP2S2HCw55xx4oxjic2Sc87hcVjz4QcHfrbZ2PMdP3zwwY8yucT+5sMHP7wpw+MwCJBA5jA2EFQ/CkbBKBgFowA/AACaz1Lb3lJPPAAAAABJRU5ErkJggg==","orcid":"","institution":"The University of Texas Health Science Center at Tyler","correspondingAuthor":true,"prefix":"","firstName":"Steven","middleName":"","lastName":"Idell","suffix":""}],"badges":[],"createdAt":"2026-04-07 17:38:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9348224/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9348224/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106637360,"identity":"6ebaa643-9f6d-4ef0-8dc7-7919c7f3d226","added_by":"auto","created_at":"2026-04-10 17:01:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":178091,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA. Planned Trial Design.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB. Trial Flow Chart\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLegend. \u003c/strong\u003eiDMC: Independent data monitoring committee. DLT: Dose limiting toxicity. N: numbers of patients per group.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9348224/v1/b9d93a9a94be21f083bd4155.png"},{"id":106637361,"identity":"e5cebba6-10ef-42b5-940f-f1e0a521c52e","added_by":"auto","created_at":"2026-04-10 17:01:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":46294,"visible":true,"origin":"","legend":"\u003cp\u003eForest Plot of Odds Ratio Using Different Treatment Failure Definitions\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLegend. \u003c/strong\u003eN=number of patients in the LTI-01 groups.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9348224/v1/08717eddd30db13ae3fe25f6.png"},{"id":106637362,"identity":"14f5f268-427f-43fd-8b7f-1b159eaef9dd","added_by":"auto","created_at":"2026-04-10 17:01:06","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":42832,"visible":true,"origin":"","legend":"\u003cp\u003eRelative Change in Pleural Opacity Volume by Dose Group\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLegend. \u003c/strong\u003eRed line represents the median value. POVOL: pleural opacity volume.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9348224/v1/2f67c978b8b9438b7bc116b4.png"},{"id":106727080,"identity":"cbd43726-3a28-4e28-a583-15383e3d02bb","added_by":"auto","created_at":"2026-04-12 18:38:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2939666,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9348224/v1/af47689a-570d-4bed-ad5d-f9c1452066a4.pdf"},{"id":106637363,"identity":"978b2b73-c79f-4187-9721-73372f63ed2e","added_by":"auto","created_at":"2026-04-10 17:01:06","extension":"xls","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":115200,"visible":true,"origin":"","legend":"","description":"","filename":"JCIPaperShoemakerIdelCRAXLS.xls","url":"https://assets-eu.researchsquare.com/files/rs-9348224/v1/9112d96f41233159835150c9.xls"}],"financialInterests":"Competing interest reported. Competing interests. Dr. Idell founded Lung Therapeutics, Inc. (LTI), which was acquired by Aileron, Inc, now called Rein Therapeutics, Inc. He has an equity position in Rein and received compensation as Chief Scientific Officer for LTI until about 2021. He remains a consultant for LTI, paid through about 2021. His declared conflicts of interest are managed through the UTHSCT and the UT System. He is an inventor on a relevant patent (USPTO 7332469) held by the UT Board of Regents and licensed to LTI. Dr Rahman has received consultancy fees from Lung Therapeutics, Inc. Dr. Windsor is President and Chief Executive Officer at Rein Therapeutics Inc. rebranded from Aileron, Inc., which acquired LTI and LTI before that, and is a director (since 2013) who receives equity and financial compensation for his roles at the company. Dr. Kurman has received grants from Biodesix, CSA Medical, Galvanize, Medtronic, Nuvaira, PrognomiQ, Pulmonx, and Veracyte and has served as a consultant for Ambu, Biodesix, Circulogene, Cook, Galvanize, Intuitive, Medtronic, Merit, Noah Medical, Pinnacle Biologics, PrognomiQ, Pulmonx, Steris, Veracyte, and Verona Pharma. Dr. Musani has served as a consultant for Intuitive. He has received research grants from Galvanize, Pinnacle, Veracyte, and Biodesix and has shares in EON. ICJME conflict of interests forms are available for each author in the supplemental material.","formattedTitle":"The LTI-01-2001 Phase 2 Trial of Intrapleural LTI-01 in Patients with Infected, Non- Draining Pleural Effusions","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eIntrapleural organization with fibrinous loculations can impair pleural drainage and negatively impact outcomes of infectious pleural diseases such as empyema or complicated parapneumonic pleural effusions (CPE)[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. For over seventy-five years, intrapleural enzymatic therapy (IET) has been used as an adjunct to antibiotics and chest tube drainage to clear loculated collections of inflammatory pleural fluid, expedite drainage and improve clinical outcomes[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].IET is now often used prior to surgical referral or in patients who are not surgical candidates, but treatment failure can occur in up to 25% of patients and IET dosing is empiric[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. At present, the combination of tPA and DNase is most common form of IET, based on efficacy demonstrated in the MIST2 clinical trial[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSingle chain urokinase (scuPA) is a proenzyme that exhibits Plasminogen Activator Inhibitor-1 (PAI-1) resistant properties that contributes to its ability to effectively and safely clear fibrinous pleural collections in rabbit models of pleural loculation and empyema[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. With the support of a Science Moving TowArds Research Translation and Therapy (SMARTT) contract (HHSN268201100014C) from the NHLBI, the expression of scuPA in Chinese Hamster Ovarian (CHO) cells was improved and toxicology studies were done to support approval of a clinical trial testing program that was initiated by Lung Therapeutics Incorporated (LTI), which continued to optimize expression and stability of the scuPA drug product, called LTI-01. In a phase 1 clinical dose ranging clinical trial performed in Australia, LTI-01 proved to be safe in a phase 1 trial of patients with empyema/CPE and failed pleural drainage[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. To our knowledge, this was the first dose ranging trial of IET in the field and hints of efficacy were observed.\u003c/p\u003e \u003cp\u003eHere, we report the results of the phase 2a trial of intrapleural LTI-01 in patients with empyema/CPE and failed pleural drainage. This was a multicenter, double blind, randomized, placebo-controlled, multicenter, dose-ranging study in hospitalized subjects with infected, non-draining pleural effusions conducted in the US from September 2020 to March 2022 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). A range of clinical outcomes, including treatment failure or mortality and pleural opacification change were assessed to enable larger scale clinical trial testing of the ability of intrapleural LTI-01 to expedite drainage of pleural fluids and improve the clinical status of patients with infected, non-draining pleural effusions. A key objective prior to trial initiation was also to identify an effective dose(s) with a favorable benefit risk profile to enable Phase 2b or 3 dosing of LTI-01 administered intrapleurally in patients with infected, non-draining pleural effusions.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003eSex as a biologic variable. \u003c/strong\u003eBoth male and female subjects were included in this study, as shown in Table 1. The findings were anticipated to be relevant to each sex, as pleural infections and complications occur in both.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Design. \u003c/strong\u003eThis was a phase 2a randomized, double-blind, placebo-controlled, multi-center, dose- ranging study conducted in hospitalized subjects at 18 sites in the US with infected, non-draining pleural effusions due to empyema/CPE. The trial was sponsored by Lung Therapeutics, Inc. (LTI) using company resources. The findings from the Phase 1 study supported further clinical development in the LTI-01-2001 and the trial design is illustrated (Figure 1). Planned trial enrollment and the dosing range are shown in Figure 1A and the trial flow chart is shown in Figure 1B. Monitoring for dose limiting toxicity (DLT) was done by the iDMC. LTI held the investigational IND for this trial, which was conducted between September of 2020 and July of 2022 with last update in March of 2023. The ClinicalTrials.gov registration number is NCT04159831. The authors designed or performed the trial, analyzed and archived the data, made the decision to submit the publication and vouch for the accuracy of the data and analyses. The study protocol is included in the Supplement to this article. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient Eligibility, Inclusion and Exclusion Criteria. \u003c/strong\u003eEligible patients met all of the following inclusion criteria (Please refer to Supplement Study Protocol for details) : 1) Male or female \u0026ge; 18 years of age 2) Clinical presentation compatible with CPE, empyema or other type of pleural infection 3) Pleural fluid requiring drainage as determined by chest ultrasonography, chest radiograph or chest CT which was either purulent, gram stain positive, culture positive, or pH \u0026lt; 7.2, glucose \u0026lt; 60 mg/dL (3.3 mmol/L). All patients had failure to adequately drain pleural fluid at least 3 hours after insertion of patent chest tube within the pleural space, as evidenced by 1 or more of the following criteria: 1) \u0026gt; 2 cm depth of fluid by ultrasound, chest radiograph or chest CT 2) \u0026lt; 80% drainage by chest radiograph compared with that obtained prior to chest tube. Exclusion related criteria included prior therapy with IET, fibrothorax, non-expandable lung preceding the present infectious episode and known malignant pleural effusions. Bleeding related exclusions included full anticoagulation, active bleeding or major trauma within 30 days. A full description of all exclusion criteria is provided in the Trial Protocol in the Supplement. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRandomization, Monitoring and Outcomes. \u003c/strong\u003eRandomization occurred using an Interactive Response Technology that notified unblinded pharmacy personnel of the dose assignment for specific study patients. Eligible patients were randomized in a 1:1:1:1 ratio to 1 of 4 dosing arms: placebo (intrapleural saline), 400,000 Units (U), 800,000 U or 1,200,000 U of LTI-01 with 25 - 40 patients per arm planned (100 \u0026ndash; 160 patients total), in a double blinded fashion (investigators and patients). After the first 12 patients were randomized, subsequent patients were stratified for randomization based upon RAPID score to assess severity of the illness attributable to pleural infection.[9] Patients received once-daily doses of study medication (LTI-01 or placebo) administered intrapleurally on Days 1, 2 and 3. Patients were monitored daily until hospital discharge for continued, non-improving pleural infection and inadequate pleural fluid drainage. Patients who required alternative pleural therapy (tPA/DNase or surgical intervention) due to worsening or non-improving infected, non-draining pleural effusion, were considered treatment failures. Treatment failure in patients requiring alternative pleural therapy was defined as meeting protocol-specified criteria for surgical referral irrespective of subsequent treatment. In the event of treatment failure, patients were assessed by chest CT prior to surgery or initiation of alternative therapy; use of an alternative agent or surgical intervention. Treatment failures were communicated to the Sponsor Medical Monitor within 24 hours of referral to surgery or initiation of additional treatment. Documentation included confirmation of protocol-defined criteria for surgical referral or the rationale for surgical referral in its absence. It should also be noted that the treating clinicians were not restricted from treating subjects according to their own assessments to ensure that subjects were receiving safe and effective therapy in this placebo-controlled trial. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary Endpoint.\u003c/strong\u003e The primary efficacy endpoint was the Incidence of treatment failure or death within 7 days of starting study medication with treatment failure defined as requiring alternative pleural therapy and meeting protocol-specified criteria for surgical referral irrespective of subsequent treatment. Protocol-specified criteria for surgical referral included:\u003cu\u003e \u003c/u\u003eFailure of complete pleural drainage as evidenced by \u0026gt; 2 cm pleural density assessed by chest computerized tomography (CT), chest radiograph or ultrasound. clinical \u003cu\u003eAND\u003c/u\u003e evidence of ongoing systemic inflammatory response syndrome (SIRS) or pleural sepsis defined as \u0026ge; 2 of: 1) Body temperature \u0026gt; 38\u0026deg;C or \u0026lt; 36\u0026deg;C for at least 2 observations in a 24-hour period 2) Heart rate \u0026gt; 90 beats per minute (BPM) for at least 2 observations in a 24-hour period 3) Respiratory rate \u0026gt; 20 breaths per minute or partial pressure of carbon dioxide in arterial blood (PaCO2) \u0026lt; 32 mmHg 4) White blood cell (WBC) count \u0026gt; 12,000/mm3, \u0026lt; 4,000/mm3 or \u0026gt; 10% bands 5) Systolic blood pressure (SBP) \u0026lt; 100 or SBP drop \u0026ge; 30 mmHg for at least 2 observations in a 24-hour period 6) C-reactive protein (CRP) \u0026lt; 50% reduced from study baseline. Two other prespecified primary analyses were also performed to assess the ability LTI-01 to affect the primary endpoint. The first was an analysis done by an iEAC assessment of treatment failure. The iEAC consisted of two academic interventional pulmonologists from the UK and one thoracic surgeon from Canada. In a second prespecified endpoint analysis, treatment failure was defined as requiring rescue therapy as determined by the treating physician. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary endpoints\u003c/strong\u003e included absolute and relative change from baseline in pleural opacity volume assessed by chest CT at Day 4 or prior to initiation of alternative pleural therapy in the event of treatment failure. If a patient was considered a treatment failure on Day 3, approximately 24 hours after the second dose of study drug, the third dose of study drug was not administered, and a follow-up chest CT was performed on Day 3 before rescue therapy was initiated. Total number of hospitalization days from randomization to hospital discharge was assessed as well as mortality at 30 days. A complete description of the secondary efficacy endpoints is included in the study protocol included in the Supplement. Safety assessments included clinical bleeding and other adverse events (AE) with severity ratings based on National Cancer Institute\u0026rsquo;s Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy medication. \u003c/strong\u003eLTI-01 is a recombinant, human scuPA that has been cloned into CHO cells. It is formulated as a lyophilized powder designed for reconstitution with approximately 2.15 mL of sterile water for injection. The formulation is packaged in a 10 mL USP Type 1 glass vial (13 mm neck) finished with a chlorobutyl rubber stopper and sealed with an aluminum overseal with a flip-off cap. The reconstituted product is a sterile, single-use solution containing approximately 400,000 U in a formulation of 20 mM sodium citrate, 50 mM sodium chloride and 15 mg/mL mannitol, pH 4.5. Placebo is 0.9% sodium chloride for injection (USP Normal Saline). LTI-01 is designed to be stored at -20 \u0026plusmn; 5 \u0026deg;C prior to use. Vials were reconstituted with approximately 2.15 mL sterile water, then brought to 6 ml with saline in a single syringe for thoracostomy tube administration followed by administration of 24 ml saline (30 ml total instillate), after which the tube was clamped for 3 hr., then reopened.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analyses. \u003c/strong\u003ePoint estimates and 95% confidence intervals (CI) of the Day 7 treatment failure rates were summarized for the LTI-01 dosing arms and placebo. Each LTI-01 dosing arm was compared to placebo using a two- sided test with significance level alpha of 0.05, to test the hypothesis of no difference in proportions for the primary endpoint for each of the LTI-01 dosing arms vs placebo. No adjustment for multiplicity was performed. Analyses of pleural opacification, indicative of pleural drainage, employed a two-sample t-test to test the hypothesis that the absolute change in pleural opacity in an LTI-01 group was not significantly different from that of placebo at an alpha of 0.05. The test was performed for each of the 4 groups. Additional tests were performed using one-way analysis of variance (ANOVA) to test that the absolute change in pleural opacity in an LTI-01 group is not different from that of placebo. To avoid any violations of normality assumptions, the data transformations were examined prior to analysis. The assumed response in the active dosing arms relative to placebo ranged from 15% to 25% in all considered models. Based on assumptions from the literature[5, 10, 11] and the Phase 1 study [8], a planned sample size of 25 to 40 patients per dosing arm was projected to provide 85% to 96% power for rejecting the null hypothesis of no difference in the primary endpoint between an LTI-01 dosing arm and placebo arm with an effect size ranging from 0.48 to 0.60 using a two-sided t-test with significance level alpha of 0.05. The same sample sizes were projected to support the identification of an effective dose(s) via MCP-Mod approach, with 90% power and 2.5% 1-sided significance level.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003ePatients.\u003c/strong\u003e Enrollment was limited to a total of 43 patients, of whom 40 were dosed in one of 4 groups: 400,000 U, 800,000 U, 1,200,000 U, and placebo. The target enrollment in this study of 100-160 subjects (Figure 1A) was not achieved due in large part to research restrictions related to the COVID-19 pandemic. Subjects with infected non-draining pleural effusions received intrapleural administration by chest tube of study drug or placebo once daily for up to 3 days (please see Supplement, study protocol for details). Demographics of the study subjects are shown in Table 1. The primary analysis in Study LTI-01-2001 was conducted once all 40 enrolled subjects had completed their Day 30 assessments. Recruitment was put on hold, and safety was reviewed by the independent Data Monitoring Committee (iDMC) after 3 subjects had been entered into each dosing arm (12 subjects total) given that the 1,200,000 LTI-01 dose had not be studied previously. The iDMC determined that no tolerability issues had occurred. Dosing then proceeded in the four-dose groups as described In the Patient\u0026rsquo;s section above.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary outcome: protocol defined treatment failure.\u0026nbsp;\u003c/strong\u003eThere was no significant difference in incidence of treatment failure within 7 days of initiation of treatment between LTI-01 and placebo groups using the protocol definition of treatment failure (Table 2). When all patients treated with any dose of LTI-01 were considered, 11/29; 37.9% of patients experienced protocol-defined treatment failure while a comparable 4/11; 36% of placebo-treated patient had treatment failure. There were no deaths in any patients through 7 days of follow-up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe protocol defined treatment failure as requiring alternative pleural therapy and meeting protocol-specified criteria for surgical referral irrespective of subsequent treatment. These criteria included at least 2 signs of ongoing systemic inflammatory response syndrome (SIRS) or pleural sepsis and inadequate pleural fluid drainage. Examples of limitations concerning the protocol checklist are described in the Supplement.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePre-specified Sensitivity Analysis 1: independent Endpoint Assessment Committee (iEAC) assessment of treatment failure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe iEAC evaluated blinded patient profiles that included brief demographic information, concomitant medications, pleural fluid characteristics, graphical representations of the SIRS/pleural sepsis criteria and had access to the baseline and follow-up CT scan images. The iEAC did not have access to site identification information, chest tube drainage information, or chest CT pleural opacity volume assessments made by a central reader. Examples of limitations of iEAC assessment in case examples are described in the Supplement. Based on this analysis, the 400,000 U LTI-01 group approached statistical significance versus placebo controls (1 treatment failure/10 subjects, OR 0.09, CI 0.01-1.02, P=0.052), while no other LTI-01 group demonstrated better outcomes by 7 days after initiation of LTI-01.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePre-specified Sensitivity Analysis 2: Treatment failure defined as requiring rescue therapy as determined by the treating physician\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the second prespecified endpoint analysis, treatment failure was defined as needed for rescue therapy (other IET or surgery) as determined by the treating physician at 7 days, the 400,000 U and 800,000 U LTI-01 dose groups showed nonsignificant trends towards improved outcomes. The placebo incidence of treatment failure was 72.7%. \u0026nbsp;That of the 400,000 U group was 40% (OR 0.26, 95% CI, 0.04-1.61, P=0.147). The 800,000 U incidence was 44.4% (OR 0.31, 95%, CI 0.05-2.02, p=0.221). A Forrest Plot of the primary outcome analyses of LTI-01 dosing groups versus placebo are illustrated in Figure 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIncidence of Surgery at Day 30.\u0026nbsp;\u003c/strong\u003eData collected for the endpoint captured actual surgery rather than referral for surgery (Table 3) through Day 30. \u0026nbsp;The incidence of surgery at Day 30 rate was highest for placebo (45.5%) compared to the LTI-01 treated groups; LTI-01 400,000 U group: 30.0%, LTI-01 800,000 U group: 22.2%, LTI-01 1,200,000 U group: 10.0%, and LTI-01 group composite: 20.7%). Chi square=0.12 all LTI-01 groups combined versus placebo.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eChanges in pleural opacification.\u0026nbsp;\u003c/strong\u003eChange from baseline in pleural opacity volume at Day 4 was the key secondary efficacy endpoint since drainage of infected pleural fluid is a key element in controlling the source of the infection along with the administration of appropriate antibiotic therapy. The change in pleural opacity volume was assessed by chest CT by measuring the volumetric size (absolute size in liters) and relative percentage change in opacification of the infected pleural effusion at baseline and after treatment with study drug, indicating how much pleural fluid drained.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFigure 2 shows that most subjects in all LTI-01 groups had a relative decrease from baseline in pleural opacity with a trend toward maximally decreased opacification in the 800,000 LTI-01 group. The outlier in the 800,000 U dose group had a 123% increase in pleural opacity volume presented with an esophageal perforation and pleural fluid characteristics suggesting leakage of swallowed oral secretions into the pleural space.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor statistical comparisons, a ranked based ANCOVA was used as pre-specified in the trial statistical analysis plan since the normality assumption was not met. The 400,000 U and 800,000 U and overall LTI-01 dose groups showed a significant difference from placebo in absolute change of pleural opacity volume (p\u0026lt; 0.05) and similar trend with relative change from baseline pleural opacity volume (p-values 0.082 and 0.064, respectively), shown in Table 4.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelationship of changes in pleural opacification and clinical outcomes.\u0026nbsp;\u003c/strong\u003eTables 5 and 6 illustrate that the relative change from baseline in pleural opacity volume can be divided into quartiles with Quartile 1 being the 25% of subjects with the largest decrease and Quartile 4 represents the 25% with the smallest decrease. Table 6 illustrates that there was a significant correlation between treatment failure and pleural opacity volume change (p-values \u0026lt;0.05), i.e. higher incidence of treatment failure is associated with smaller pleural opacity volume reduction. Based on these considerations, Quartile 4 subjects with the smallest relative decrease in pleural opacity volume had a 90% treatment failure rate in contrast to Quartile 1 subjects with the largest relative decrease in pleural opacity volume who had a 20% treatment failure rate. \u0026nbsp; Based on this analysis, pleural opacity volume was indicative of the need for rescue therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePleural fluid drainage.\u0026nbsp;\u003c/strong\u003eAn exploratory endpoint in this trial was to assess the daily amount of fluid draining out of the chest tube. The mean cumulative fluid drainage was greater in the LTI-01 groups when at 1, 2 and 3d after initiation of LTI-01 IET compared to the placebo-treated patients but these trends did not achieve significance versus placebo (Table 7).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety Analyses.\u0026nbsp;\u003c/strong\u003eBased on the analysis of treatment emergent adverse events (TEAEs) in the LTI-01 groups, there were no safety signals of concern (Table 8) and specifically no episodes of intrapleural or systemic bleeding events assessed as related to study drug (Table 9). Of note, there were no serious TEAEs related to study drug in any of the treatment groups. In the LTI-01 groups, 77.8% of TEAEs were unrelated to the agent. The most frequently occurring TEAEs (treatment emergent adverse events) were chest pain (4 subjects), constipation (4 subjects), and diarrhea (4 subjects) followed by insomnia (3 subjects). Five subjects died during the follow-up period up to 6 months after active dosing. No death was attributed to LTI-01 treatment. Additional details about each of these patients and of patients experiencing TEAEs is included in the Supplement.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis was, to our knowledge, the first-ever dose-ranging, randomized, double-blind, placebo-controlled, efficacy trial of a form of IET; LTI-01. The trial was performed at 18 US institutions in hospitalized subjects with infected, non-draining pleural effusions. The study was completed with last patient, last visit (Day 180) in July 2022. The intended enrollment was 25\u0026ndash;40 subjects per arm (100\u0026ndash;160 total with 3 LTI-01 doses and placebo). Enrollment was limited to 43 subjects due in large part to the COVID-19 pandemic, of which 40 subjects were dosed and included in the safety and efficacy analysis. While the use of a placebo group and study design may have contributed to this problem, we believe that resources and manpower allocations for the care of large numbers of COVID-19 patients were mainly responsible for limited enrollment.\u003c/p\u003e \u003cp\u003eThe analysis and interpretation of this study are thus constrained by relative paucity of enrollment and available data. There were no significant differences between any LTI-01 group and placebo-treated patients in the incidence treatment failure or death within 7 days using the protocol definitions. However, important findings including significant and nonsignificant efficacy signals of LTI-01 compared with placebo were found when considering the totality of the data. These findings also bear implications for the design of a future Phase 2b study in which better efficacy assessments can derive from larger treatment cohorts.\u003c/p\u003e \u003cp\u003eThe protocol defined failure as requiring alternative pleural therapy and meeting protocol-specified criteria for surgical referral irrespective of actual subsequent treatment. The criteria included at least 2 signs of ongoing systemic inflammatory response syndrome (SIRS) or pleural sepsis and inadequate pleural fluid drainage, which to our knowledge have not been used previously as part of a drug development program targeting regulatory approval. Because these criteria had not been assessed previously, subjects requiring rescue therapy were considered treatment failures that were discussed with the medical monitor and prespecified sensitivity analyses were performed, one by the iEAC and the other based on the treating physician\u0026rsquo;s assessment that alternative treatment (either other IET or surgery) was required. The iEAC assessment concluded that the 400,000 U LTI-01 dose resulted in less treatment failure than the placebo group, while the rescue treatment sensitivity analysis revealed nonsignificant trends towards reduced treatment failure in the 400,000 or 800,000 LTI-01 versus placebo groups (Please see outcome sensitivity analysis sections, Results). These findings support further testing in a larger phase 2b trial.\u003c/p\u003e \u003cp\u003eThe discordance between protocol checklist outcomes and iEAC sensitivity analysis outcomes triggered a reexamination of The Phase 2 protocol checklist criteria for defining treatment failure, which were found to have limitations. Situations in which subjects required surgery for evolving pleural fibrosis or trapped lung were not well captured by the protocol definition and in two placebo and one LTI-01 1.2\u0026nbsp;million U dose patients, rescue surgeries were performed despite meeting criteria as protocol treatment successes. These were, however, designated as treatment failures by iEAC and rescue therapy sensitivity analyses, accounting for some of the disparate conclusions. The iEAC assessments also had incomplete clinical information that appeared to have resulted in different conclusions, one in the 400,000 U and another in a patient in the 800,000 U LTI-01 group, which further contributed to the disparities. The sensitivity analyses are intriguing, clinically germane and supportive of clinical efficacy but do not obviate the protocol defined outcomes showing no difference in treatment failure. In a related outcome assessment, there was a decrement in the incidence in actual surgeries in the LTI-01 treatment versus placebo groups. Although the trends did not achieve statistical significance, more surgeries were done in the placebo versus LTI-01 groups. In the aggregate, we infer that analyses of treatment groups with larger numbers are required to reach conclusions about the efficacy of LTI-01 for non-draining empyema/CPE. In addition, protocol adjustments that better square the requirement for surgery of trapped lung or rescue IET will need to be incorporated into the study design of future trials.\u003c/p\u003e \u003cp\u003eChanges in pleural opacification are important indicators of the efficacy of pleural drainage and there is clear evidence that they relate to the ability of IET to improve clinical outcomes. The findings of the MIST2 and MIST3 trials in particular strongly suggest that reduction of pleural opacification relates to clinically important outcome such as referral to surgery or length of hospital stay or quality of life[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In this trial, the absolute reduction in pleural opacification determined by noncontract chest CT imaging achieved statistical significance for both the 400,000U and 800,000U LTI-01 treated patients versus placebo (Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). The reduction of relative pleural opacification versus baseline approached statistical significance for the same groups, with the greatest relief or opacification observed in the 800,000 U treated patients (Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). There was no difference in pleural opacification in the 1,200,000 U LTI-01 group versus placebo. Differences in disease severity, suggested by the highest RAPID scores in this group or differences in aberrant intrapleural fibrin turnover or profibrogenic mediator expression may have been contributory. It is conceivable that all these factors could have influenced opacification readouts at the 1.200,000U dose of LTI-01 but this dose appears to have little predicate for future clinical trial testing. Based on the findings, a 400,000 or 800,000U dose of intrapleural LTI-01 may be considered for future clinical trial testing.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWhile relative pleural opacification was extrapolated from chest X-rays in MIST2 and directly measured by chest CT in this study, the magnitude of change was greater in the LTI-01 800,000 group (-55.8%) versus placebo (-16.1%) (than that previously reported in MIST2 (tPA/DNase\u0026thinsp;\u0026minus;\u0026thinsp;29.5, placebo\u0026thinsp;\u0026minus;\u0026thinsp;17.2%). Caveats include measurement of medians of relative opacification in this trial versus means+/- standard deviations in MIST2, much larger patient groups of about 50 patients/group, 200 total in MIST2 and measurement of pleural opacification at day 7 in MIST2 [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] versus at day 4 in the present study. However, we believe that the data supports further evaluation of the effects of LTI-01 on pleural opacification in a future phase 2b trial.\u003c/p\u003e \u003cp\u003ePleural fluid evacuation increases after administration of tPA/DNase-based IET and occurs in conjunction with reduction of sequestered intrapleural fluid collections[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The same trends in thoracostomy tube drainage and relative pleural opacification were found by either CXR or CT imaging in a limited number of patients (n\u0026thinsp;=\u0026thinsp;14) who received LTI-01 50,000-800,000 U LTI-01 daily over 3 days in our preceding phase 1 trial[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Trends of increased chest tube drainage were similarly observed in this study at each dose of intrapleural LTI-01 (Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e) and we speculate that the relatively low numbers of patients evaluated contributed to the lack of statistically significant increments. Surprisingly, cumulative thoracostomy drainage was not increased in the 1.2\u0026nbsp;million U LTI-01 treatment group, consistent with the inability of this dose to approach significant improvement of absolute or relative pleural opacification.\u003c/p\u003e \u003cp\u003eThe relationship between reduced pleural opacification and other clinical outcomes in IET trials remains a point of interest. While we acknowledge that changes in pleural opacification are a surrogate outcome, there is evidence now that other clinical outcomes including hospital length of stay, referral or performance of surgery and extended mortality; 30 or more days beyond IET are related to improvement in pleural opacification.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] We stratified the levels of pleural opacification by quartiles (Fig.\u0026nbsp;7A) after which we determined that the severity of opacification was significantly related to treatment failure (Fig.\u0026nbsp;7B). While the analysis is still limited by the relatively low numbers of patient responses evaluated (N\u0026thinsp;=\u0026thinsp;40), it lends further support for the concept that changes in pleural opacification by IET relate to clinically meaningful outcomes.\u003c/p\u003e \u003cp\u003eThe safety assessments consolidate the favorable adverse event profile that we observed in the phase 1 LTI-01 dose ranging study.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] Importantly, no bleeding events were again observed, attesting to the safety of administration of intrapleural LTI-01, including the highest 1,200,000U dose that exceeded this tested in phase 1. It is possible that the intrapleural processing of the proenzyme scuPA may offer advantages versus delivery of an active serine protease such as tPA[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile pleural fluid analyses can offer insight into individual responses to treatment[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], group trends could be obviated by the low numbers available in this study. It would be anticipated that plasminogen activator inhibitor-1; PAI-1, (the major inhibitor of pleural fluid plasminogen activator activity) levels and activity are most elevated in patients prone to treatment failure, as PAI-1 increases intrapleural septation, decreases pleural drainage and extends length of stay and mortality assessed over 30 days [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Single chain uPA generated by LTI-01 as a part of its intrapleural processing, it could induce mesothelial cell TGF-β and Tissue Factor (TF) expression. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] Increased intrapleural TGF-β promotes intrapleural organization and fibrosis [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], as does TF [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Dedicated biochemical studies are comprehensive, labor intensive and outside the scope of this report, but we plan to conduct such analyses on pleural fluids from patients in this trial and share the findings in the future.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eThis trial offers several considerations that can potentially advance the field. This is the only dose-ranging phase 2 study of a form of IET of which we are aware and the first efficacy trial in which efficacy of LTI-01 was tested. This trial design enables the discovery of counter-intuitive responses to IET, as we observed with lack of reduction of pleural opacification in patients treated with 1,200,000 U LTI-01. Dosing of IET agents can be refined in a data-driven manner using this format, which addresses some of the empiricism that surrounds the current use of IET[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The favorable safety profile of LTI-01 IET originally identified in phase 1 testing was sustained in this trial and may offer advantages over tPA/DNase bleeding rates of about 4 percent.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] The favorable reductions of pleural opacification and evidence of its relationship to reduced treatment failure support further evaluation of LTI-01 IET in a properly powered phase 2b study, which is feasible and now being planned.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eLTI-01- recombinant single chain urokinase plasminogen activator, IET- intrapleural enzymatic therapy, PAI-1- plasminogen activator inhibitor 1, TGF-\u0026beta;- transforming growth beta 1, TF- tissue factor, TEAE: treatment-emergent adverse event, National Cancer Institute\u0026rsquo;s Common Terminology Criteria for Adverse Events (CTCAE).\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eHuman Ethics and Consent to Participate.\u0026nbsp;\u003c/strong\u003eThis study received Institutional Review Board approval from all participating institutions prior to study initiation. All subjects provided written informed consent prior to participation. This trial was conducted in accordance with ethical principles from the Declaration of Helsinki, and clinical research guidelines established by the United States Code of Federal Regulations (21 CFR Parts 50, 56, and 312) and the International Conference on Harmonisation (ICH) E6(R1) Guideline for Good Clinical Practice (GCP).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication.\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials.\u0026nbsp;\u003c/strong\u003eAll resource data generated or analyzed during this study are included in the supplementary data in an Excel file format. The trial protocol, supplemental patient data and individual author competing interest attestations are also available in the supplement that accompanies this report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests.\u0026nbsp;\u003c/strong\u003eDr. Idell founded Lung Therapeutics, Inc. (LTI), which was acquired by Aileron, Inc, now called Rein Therapeutics, Inc. He has an equity position in Rein and received compensation as Chief Scientific Officer for LTI until about 2021. He remains a consultant for LTI, paid through about 2021. His declared conflicts of interest are managed through the UTHSCT and the UT System. He is an inventor on a relevant patent (USPTO 7332469) held by the UT Board of Regents and licensed to LTI. Dr Rahman has received consultancy fees from Lung Therapeutics, Inc. Dr. Windsor is President and Chief Executive Officer at Rein Therapeutics Inc. rebranded from Aileron, Inc., which acquired LTI and LTI before that, and is a director (since 2013) who receives equity and financial compensation for his roles at the company. Dr. Kurman has received grants from Biodesix, CSA Medical, Galvanize, Medtronic, Nuvaira, PrognomiQ, Pulmonx, and Veracyte and has served as a consultant for Ambu, Biodesix, Circulogene, Cook, Galvanize, Intuitive, Medtronic, Merit, Noah Medical, Pinnacle Biologics, PrognomiQ, Pulmonx, Steris, Veracyte, and Verona Pharma. Dr. Musani has served as a consultant for Intuitive. He has received research grants from Galvanize, Pinnacle, Veracyte, and Biodesix and has shares in EON. ICJME conflict of interests forms are available for each author in the supplemental material.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding.\u0026nbsp;\u003c/strong\u003eLung Therapeutics, Inc.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e: CRL, JA, AM, SS, AC, JK, PJ, MS, DA, MW, SA. M A-H, KM, JP, LY, FK, FM and GC recruited patients, obtained informed consent, managed trial patients and assisted with the writing and review of the manuscript. BW helped develop the study and oversaw the sponsor\u0026rsquo;s financial and logistic commitments to the trial. NMR consulted on trial design, protocol development, review of the data and writing of the manuscript. CA and KPS performed statistical analyses and reviewed the manuscript. SS organized the trial design, protocol, trial data archive, reviewed the data related to the trial and contributed to writing of the manuscript. SI contributed to the trial design and trial data and its interpretation and wrote the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements.\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; information.\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFootnotes.\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr clear=\"all\"\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKomissarov AA, Rahman N, Lee YCG, Florova G, Shetty S, Idell R, Ikebe M, Das K, Tucker TA, Idell S: \u003cstrong\u003eFibrin turnover and pleural organization: bench to bedside.\u003c/strong\u003e \u003cem\u003eAm J Physiol Lung Cell Mol Physiol \u003c/em\u003e2018, \u003cstrong\u003e314:\u003c/strong\u003eL757\u0026ndash;L768.\u003c/li\u003e\n\u003cli\u003eTillett WS, SHERRY S: \u003cstrong\u003eTHE EFFECT IN PATIENTS OF STREPTOCOCCAL FIBRINOLYSIN (STREPTOKINASE) AND STREPTOCOCCAL DESOXYRIBONUCLEASE ON FIBRINOUS, PURULENT, AND SANGUINOUS PLEURAL EXUDATIONS.\u003c/strong\u003e \u003cem\u003eJ Clin Invest \u003c/em\u003e1949, \u003cstrong\u003e28:\u003c/strong\u003e173\u0026ndash;190.\u003c/li\u003e\n\u003cli\u003eSiddiqui HA, Maginot ER, Moody TB, Henry R, Barrett CD: \u003cstrong\u003ePleural Space Diseases and Their Management: What is the Role of Intrapleural Fibrinolytic Therapy?\u003c/strong\u003e \u003cem\u003eAm Surg \u003c/em\u003e2025, \u003cstrong\u003e91:\u003c/strong\u003e1036\u0026ndash;1045.\u003c/li\u003e\n\u003cli\u003eIdell S, Rahman NM: \u003cstrong\u003eIntrapleural Fibrinolytic Therapy for Empyema and Pleural Loculation: Knowns and Unknowns.\u003c/strong\u003e \u003cem\u003eAnn Am Thorac Soc \u003c/em\u003e2018, \u003cstrong\u003e15:\u003c/strong\u003e515\u0026ndash;517.\u003c/li\u003e\n\u003cli\u003eRahman NM, Maskell NA, West A, Teoh R, Arnold A, Mackinlay C, Peckham D, Davies CW, Ali N, Kinnear W, et al: \u003cstrong\u003eIntrapleural use of tissue plasminogen activator and DNase in pleural infection.\u003c/strong\u003e \u003cem\u003eN Engl J Med \u003c/em\u003e2011, \u003cstrong\u003e365:\u003c/strong\u003e518\u0026ndash;526.\u003c/li\u003e\n\u003cli\u003eIdell S, Mazar A, Cines D, Kuo A, Parry G, Gawlak S, Juarez J, Koenig K, Azghani A, Hadden W, et al: \u003cstrong\u003eSingle-Chain Urokinase Alone or Complexed to Its Receptor in Tetracycline-induced Pleuritis in Rabbits.\u003c/strong\u003e \u003cem\u003eAm J Respir Crit Care Med \u003c/em\u003e2002, \u003cstrong\u003e166:\u003c/strong\u003e920\u0026ndash;926.\u003c/li\u003e\n\u003cli\u003eKomissarov AA, Florova G, Azghani AO, Buchanan A, Boren J, Allen T, Rahman NM, Koenig K, Chamiso M, Karandashova S, et al: \u003cstrong\u003eDose dependency of outcomes of intrapleural fibrinolytic therapy in new rabbit empyema models.\u003c/strong\u003e \u003cem\u003eAm J Physiol Lung Cell Mol Physiol \u003c/em\u003e2016, \u003cstrong\u003e311:\u003c/strong\u003eL389\u0026ndash;399.\u003c/li\u003e\n\u003cli\u003eBeckert L, Brockway B, Simpson G, Southcott AM, Lee YCG, Rahman N, Light RW, Shoemaker S, Gillies J, Komissarov AA, et al: \u003cstrong\u003ePhase 1 trial of intrapleural LTI-01; single chain urokinase in complicated parapneumonic effusions or empyema.\u003c/strong\u003e \u003cem\u003eJCI Insight \u003c/em\u003e2019, \u003cstrong\u003e5\u003c/strong\u003e.\u003c/li\u003e\n\u003cli\u003eRahman NM, Kahan BC, Miller RF, Gleeson FV, Nunn AJ, Maskell NA: \u003cstrong\u003eA clinical score (RAPID) to identify those at risk for poor outcome at presentation in patients with pleural infection.\u003c/strong\u003e \u003cem\u003eChest \u003c/em\u003e2014, \u003cstrong\u003e145:\u003c/strong\u003e848\u0026ndash;855.\u003c/li\u003e\n\u003cli\u003eDiacon AH, Theron J, Schuurmans MM, Van de Wal BW, Bolliger CT: \u003cstrong\u003eIntrapleural streptokinase for empyema and complicated parapneumonic effusions.\u003c/strong\u003e \u003cem\u003eAm J Respir Crit Care Med \u003c/em\u003e2004, \u003cstrong\u003e170:\u003c/strong\u003e49\u0026ndash;53.\u003c/li\u003e\n\u003cli\u003eHooper CE, Edey AJ, Wallis A, Clive AO, Morley A, White P, Medford AR, Harvey JE, Darby M, Zahan-Evans N, Maskell NA: \u003cstrong\u003ePleural irrigation trial (PIT): a randomised controlled trial of pleural irrigation with normal saline versus standard care in patients with pleural infection.\u003c/strong\u003e \u003cem\u003eEur Respir J \u003c/em\u003e2015, \u003cstrong\u003e46:\u003c/strong\u003e456\u0026ndash;463.\u003c/li\u003e\n\u003cli\u003eBedawi EO, Stavroulias D, Hedley E, Blyth KG, Kirk A, De Fonseka D, Edwards JG, Internullo E, Corcoran JP, Marchbank A, et al: \u003cstrong\u003eEarly Video-assisted Thoracoscopic Surgery or Intrapleural Enzyme Therapy in Pleural Infection: A Feasibility Randomized Controlled Trial. The Third Multicenter Intrapleural Sepsis Trial-MIST-3.\u003c/strong\u003e \u003cem\u003eAm J Respir Crit Care Med \u003c/em\u003e2023, \u003cstrong\u003e208:\u003c/strong\u003e1305\u0026ndash;1315.\u003c/li\u003e\n\u003cli\u003ePiccolo F, Pitman N, Bhatnagar R, Popowicz N, Smith NA, Brockway B, Nickels R, Burke AJ, Wong CA, McCartney R, et al: \u003cstrong\u003eIntrapleural tissue plasminogen activator and deoxyribonuclease for pleural infection. An effective and safe alternative to surgery.\u003c/strong\u003e \u003cem\u003eAnn Am Thorac Soc \u003c/em\u003e2014, \u003cstrong\u003e11:\u003c/strong\u003e1419\u0026ndash;1425.\u003c/li\u003e\n\u003cli\u003eKomissarov AA, Florova G, Azghani A, Karandashova S, Kurdowska AK, Idell S: \u003cstrong\u003eActive alpha-macroglobulin is a reservoir for urokinase after fibrinolytic therapy in rabbits with tetracycline-induced pleural injury and in human pleural fluids.\u003c/strong\u003e \u003cem\u003eAm J Physiol Lung Cell Mol Physiol \u003c/em\u003e2013, \u003cstrong\u003e305:\u003c/strong\u003eL682\u0026ndash;L692.\u003c/li\u003e\n\u003cli\u003eBedawi EO, Kanellakis NI, Corcoran JP, Zhao Y, Hassan M, Asciak R, Mercer RM, Sundaralingam A, Addala DN, Miller RF, et al: \u003cstrong\u003eThe Biological Role of Pleural Fluid PAI-1 and Sonographic Septations in Pleural Infection: Analysis of a Prospectively Collected Clinical Outcome Study.\u003c/strong\u003e \u003cem\u003eAm J Respir Crit Care Med \u003c/em\u003e2022.\u003c/li\u003e\n\u003cli\u003eLee YC, Lane KB, Zoia O, Thompson PJ, Light RW, Blackwell TS: \u003cstrong\u003eTransforming growth factor-beta induces collagen synthesis without inducing IL-8 production in mesothelial cells.\u003c/strong\u003e \u003cem\u003eEur Respir J \u003c/em\u003e2003, \u003cstrong\u003e22:\u003c/strong\u003e197\u0026ndash;202.\u003c/li\u003e\n\u003cli\u003eMutsaers SE, Prele CM, Brody AR, Idell S: \u003cstrong\u003ePathogenesis of pleural fibrosis.\u003c/strong\u003e \u003cem\u003eRespirology \u003c/em\u003e2004, \u003cstrong\u003e9:\u003c/strong\u003e428\u0026ndash;440.\u003c/li\u003e\n\u003cli\u003eAkulian J, Bedawi EO, Abbas H, Argento C, Arnold DT, Balwan A, Batra H, Uribe Becerra JP, Belanger A, Berger K, et al: \u003cstrong\u003eBleeding Risk With Combination Intrapleural Fibrinolytic and Enzyme Therapy in Pleural Infection: An International, Multicenter, Retrospective Cohort Study.\u003c/strong\u003e \u003cem\u003eChest \u003c/em\u003e2022, \u003cstrong\u003e162:\u003c/strong\u003e1384\u0026ndash;1392.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Subject Demographics and Baseline Characteristics ITT Population\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"576\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCategory\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; LTI-01\u003cbr\u003e\u0026nbsp;(400,000 U)\u003cbr\u003e\u0026nbsp;N=10\u003cbr\u003e\u0026nbsp;n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01\u003cbr\u003e\u0026nbsp;(800,000 U) N=9\u003cbr\u003e\u0026nbsp;n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01 (1,200,000 U)\u003cbr\u003e\u0026nbsp;N=10\u003cbr\u003e\u0026nbsp; \u0026nbsp;n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01\u003cbr\u003e\u0026nbsp;Overall\u003cbr\u003e\u0026nbsp;N=29\u003cbr\u003e\u0026nbsp;n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo\u003cbr\u003e\u0026nbsp; \u0026nbsp;N=11\u003cbr\u003e\u0026nbsp; \u0026nbsp;n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eAge (Years) Median\u003c/p\u003e\n \u003cp\u003eMin/Max\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e58.5\u003c/p\u003e\n \u003cp\u003e36/90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e57.0\u003c/p\u003e\n \u003cp\u003e20/78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e63.0\u003c/p\u003e\n \u003cp\u003e34/87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e58.0\u003c/p\u003e\n \u003cp\u003e20/90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e66.0\u003c/p\u003e\n \u003cp\u003e44/72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eSex (n, %) Male\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e6 (60)\u003c/p\u003e\n \u003cp\u003e4 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e5 (55.6)\u003c/p\u003e\n \u003cp\u003e4 (44.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e6 (60)\u003c/p\u003e\n \u003cp\u003e4 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e17 (58.6)\u003c/p\u003e\n \u003cp\u003e12 (41.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e8 (72.7)\u003c/p\u003e\n \u003cp\u003e3 (27.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eRace: Asian (%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Black (%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;White (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;1 (10)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;1 (10)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;8 (80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;2 (22.2) \u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;6 (66.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;1 (10)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;2 (20)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;7 (70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e2 (6.9)\u003c/p\u003e\n \u003cp\u003e5 (17.2)\u003c/p\u003e\n \u003cp\u003e21 (72.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1(9.1)\u003c/p\u003e\n \u003cp\u003e10 (90.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eWeight Median\u003c/p\u003e\n \u003cp\u003eMin/Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e87.7\u003c/p\u003e\n \u003cp\u003e34.5/131.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e68.8\u003c/p\u003e\n \u003cp\u003e43.5/101.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e89.3\u003c/p\u003e\n \u003cp\u003e52.1/137.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e79.3\u003c/p\u003e\n \u003cp\u003e34.5/137.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e78.0\u003c/p\u003e\n \u003cp\u003e47.72/113.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eRAPID: Low Risk; 0-2\u003c/p\u003e\n \u003cp\u003e(%) Moderate Risk; 3-4\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;High Risk; 5-7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e5 (50)\u003c/p\u003e\n \u003cp\u003e5 (50)\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; 4 (44.4)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; 5 (55.6)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;0 \u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e3 (30)\u003c/p\u003e\n \u003cp\u003e4 (40)\u003c/p\u003e\n \u003cp\u003e3 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e12 (41.4)\u003c/p\u003e\n \u003cp\u003e14 (48.3)\u003c/p\u003e\n \u003cp\u003e3 (10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e4 (36.4)\u003c/p\u003e\n \u003cp\u003e6 (54.5)\u003c/p\u003e\n \u003cp\u003e1 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eLegend.\u0026nbsp;\u003c/strong\u003e One patient in the 800,000U group was listed as \u0026ldquo;Other\u0026rdquo; race. RAPID: Scoring system to predict outcomes after pleural infection (9). ITT: Intent to Treat.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Primary Efficacy Analysis: Incidence of Treatment Failure (Protocol Definition) Within 7 Days of Treatment.\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"603\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment Failure\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e(400,000 U)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e(800,000 U)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;(\u003c/strong\u003e\u003cstrong\u003e1,200,000 U)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll LTI-01\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=29\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eYes, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e3 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e3 (33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e5 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e11 (37.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e4 (36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eNo, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e7 (70%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e6 (66.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e5 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e18 (62.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e7 (63%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eOdds Ratio (OR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e1.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e(0.12, 4.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e(0.14, 5.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e(0.26, 9.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e(0.24, 4.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eP-value\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.782\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e0.917\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.625\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e0.958\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eLegend.\u0026nbsp;\u003c/strong\u003eCI = confidence interval\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 3. Secondary Efficacy Analysis: Logistic Regression of Incidence of Surgery at Day 30 \u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"633\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eResponse\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01 (400,000 U)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01 (800,000 U)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01 (1,200,000 U)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll LTI-01\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=29\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eIncidence of Referral to Surgery at Day 30, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e3 (30.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e2 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e1 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e6 (20.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e5 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eOdds Ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e(0.08, 3.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e(0.05, 2.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e(0.01, 1.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e(0.07, 1.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e0.459\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e0.280\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e0.113\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e0.131\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eLegend.\u0026nbsp;\u003c/strong\u003eAbbreviations: CI = confidence interval; n = Number of patients with non-missing data within the specific category, N = Number of patients; Population; RAPID\u0026nbsp;=\u0026nbsp;composite clinical mortality risk score consisting of renal, age, purulence, infection source, and dietary factors\u003c/p\u003e\n\u003cp\u003ePercentages were based on N.\u003c/p\u003e\n\u003cp\u003eThe logistic regression was performed with referral to surgery as the response variable, dose group, along with the RAPID score at randomization as the covariate.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 4: Absolute and Relative Change from Baseline of Pleural Opacity Volume\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"618\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatistics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01\u003cbr\u003e\u0026nbsp;(400,000 U)\u0026nbsp;\u003cbr\u003e\u0026nbsp; N=10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01\u003cbr\u003e\u0026nbsp;(800,000 U)\u0026nbsp;\u003cbr\u003e\u0026nbsp; N=9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01\u003cbr\u003e\u0026nbsp;(1,200,000 U)\u0026nbsp;\u003cbr\u003e\u0026nbsp; N=10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01\u003cbr\u003e\u0026nbsp;Overall\u0026nbsp;\u003cbr\u003e\u0026nbsp; N=29\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo\u0026nbsp;\u003cbr\u003e\u0026nbsp; \u0026nbsp;N=11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eAbsolute Change from Baseline (L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u0026nbsp;n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u0026nbsp;Median\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e-0.255\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e-0.280\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e-0.140\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e-0.250\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e-0.100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u0026nbsp;p-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e0.027\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e0.035\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e0.311\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e0.026\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eRelative Change from Baseline (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u0026nbsp;n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u0026nbsp;Median\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e-33.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e-55.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e-23.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e-31.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e-16.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u0026nbsp;p-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e0.082\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e0.064\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e0.466\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e0.070\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5: Quartiles for Relative Change from Baseline in Pleural Opacity Volume\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 118px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eQuartile\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRelative change\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 118px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026lt; -49.9%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 118px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u003cu\u003e\u0026gt;\u003c/u\u003e -49.9% to \u0026lt; -27.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 118px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u003cu\u003e\u0026gt;\u003c/u\u003e -27.8% to \u0026lt; -12.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 118px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u003cu\u003e\u0026nbsp;\u0026gt;\u003c/u\u003e -12.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 6: Post hoc Analysis: Quartiles of Relative Change from Baseline in Pleural Opacity Volume and Count of Treatment Failure\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eQuartiles\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value - Fisher Exact Test\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value- Cochran- Armitage Trend Test\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eQ2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eQ3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eQ4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCount of Treatment Failure Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e% Within Relative Quartiles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e20%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e60%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e90%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCount of Treatment Failure No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e% Within Relative Quartiles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e80%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e40%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal Count\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 7: Analysis of Cumulative Pleural Fluid Drainage\u0026nbsp;Via Thoracostomy Tube\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"693\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTimepoint\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatistics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01\u003cbr\u003e\u0026nbsp;(400,000 U)\u0026nbsp;\u003cbr\u003e\u0026nbsp; N=10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01\u003cbr\u003e\u0026nbsp;(800,000 U)\u0026nbsp;\u003cbr\u003e\u0026nbsp; N=9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01\u003cbr\u003e\u0026nbsp;(1,200,000 U)\u0026nbsp;\u003cbr\u003e\u0026nbsp; N=10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01\u003cbr\u003e\u0026nbsp;Overall\u0026nbsp;\u003cbr\u003e\u0026nbsp; N=29\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo\u0026nbsp;\u003cbr\u003e\u0026nbsp; \u0026nbsp;N=11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e24-hours post first dose\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(Day 2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003eLS Mean (SE)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e544.7 (122.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e577.2 (128.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e483.0 (122.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e533.5 (70.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e353.7 (116.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e(297.1 , 792.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e(316.2 , 838.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e(235.4 , 730.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e(391.7 , 675.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(117.6 , 589.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003eLS Mean Difference (SE)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e191.0 (168.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e223.5 (173.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e129.3 (168.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e179.8 (133.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e(-151.2 , 533.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e(-128.5 , 575.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e( -212.9 , 471.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e(-90.7 , 450.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e24-hours post second dose\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(Day 3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003eLS Mean (SE)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e863.0 (172.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e878.9 (172.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e776.1 (163.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e837.1 (95.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e592.4 (156.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e(512.6 , 1213.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e(528.5 , 1229.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e(443.7 , 1108.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e(643. 6 , 1030.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(275.4 , 909.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003eLS Mean Difference (SE)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e270.6 (232.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e286.5 (232.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e183.7 (226.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e244.7 (179.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e( -201.9 , 743.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e( -186.0 , 759.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e( -275.6 , 643.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e( -119.5 , 609.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e24-hours post third dose\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(Day 4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003eLS Mean (SE)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e939.6 (224.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e1125.0 (211.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e1142.0 (211.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e1073.8 (122.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e766.5 (191.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e(482.3 , 1397.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e(693.8 , 1556.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e(710.8 , 1573.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e(826.1 , 1321.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(376.4 , 1156.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003eLS Mean Difference (SE)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e173.2 (295.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e358.5 (285.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e375.5 (285.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e307.4 (223.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e( -427.9 , 774.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e(-222.9 , 939.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e( -205.9 , 957.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e(-147.0 , 761.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eLegend.\u0026nbsp;\u003c/strong\u003eCI: Confidence interval. LS Mean: Least-Squares mean values. Differences in LTI-01 treatment groups versus placebo controls are represented.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 8: Summary of Treatment Emergent Adverse Events (TEAE)s)\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"630\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCategory\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; LTI-01\u003cbr\u003e\u0026nbsp;(400,000 U)\u003cbr\u003e\u0026nbsp; \u0026nbsp; N=10\u003cbr\u003e\u0026nbsp; \u0026nbsp; n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01\u003cbr\u003e\u0026nbsp;(800,000 U)\u003cbr\u003e\u0026nbsp; \u0026nbsp; N=9\u003cbr\u003e\u0026nbsp; \u0026nbsp; n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01 (1,200,000 U)\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;N=10\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01\u003cbr\u003e\u0026nbsp; \u0026nbsp;Overall\u003cbr\u003e\u0026nbsp; \u0026nbsp; N=29\u003cbr\u003e\u0026nbsp; \u0026nbsp; n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo\u003cbr\u003e\u0026nbsp; \u0026nbsp;N=11\u003cbr\u003e\u0026nbsp; \u0026nbsp;n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall\u003cbr\u003e\u0026nbsp; \u0026nbsp;N=40\u003cbr\u003e\u0026nbsp; \u0026nbsp;n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eNumber of Subjects with TEAE\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e5 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e7 (77.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e6 (60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e18 (62.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e8 (72.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e26 (65.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eNumber of Subjects with Serious TEAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e1 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e1 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e1 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e3 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eNumber of Subjects with Treatment Related TEAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e1 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e2 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e1 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e4 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e4 (15.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eNumber of Subjects with Serious Treatment Related TEAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eNumber of Subjects with TEAE Leading to Study Drug Discontinuation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e1 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e1 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e2 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSeverity/CTCAE Grade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Grade 1 (Mild)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e2 (40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e3 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e2 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e7 (38.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e7 (87.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e14 (53.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Grade 2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;(Moderate)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e3 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e3 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e3 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Grade 3 (Severe)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e2 (40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e1 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e3 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e6 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e1 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e7 (26.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Grade 4\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;(Life threatening)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Grade 5 (Death)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e1 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e1 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e2 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRelationship to Study Drug\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Related\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e1 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e2 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e1 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e4 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e4 (15.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Not Related\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e4 (80.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e5 (71.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e5 (83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e14 (77.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e8 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e22 (84.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eLegend.\u0026nbsp;\u003c/strong\u003eTEAE: treatment-emergent adverse event, National Cancer Institute\u0026rsquo;s Common Terminology Criteria for Adverse Events (CTCAE).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Table 9: TEAEs Occurring in \u0026gt;1 Subject in LTI-01 and Placebo Groups\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"630\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; Preferred Term\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;LTI-01\u003cbr\u003e\u0026nbsp;(400,000 U)\u003cbr\u003e\u0026nbsp; \u0026nbsp; N=10\u003cbr\u003e\u0026nbsp; \u0026nbsp; n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01\u003cbr\u003e\u0026nbsp;(800,000 U)\u003cbr\u003e\u0026nbsp; \u0026nbsp; N=9\u003cbr\u003e\u0026nbsp; \u0026nbsp; n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLTI-01\u003cbr\u003e\u0026nbsp;(1,200,000 U)\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;N=10\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; LTI-01\u003cbr\u003e\u0026nbsp; \u0026nbsp;Overall\u003cbr\u003e\u0026nbsp; \u0026nbsp; N=29\u003cbr\u003e\u0026nbsp; \u0026nbsp; n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo\u003cbr\u003e\u0026nbsp; \u0026nbsp;N=11\u003cbr\u003e\u0026nbsp; \u0026nbsp;n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall\u003cbr\u003e\u0026nbsp; \u0026nbsp;N=40\u003cbr\u003e\u0026nbsp; \u0026nbsp;n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eNumber of Subjects with at Least One TEAE\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e5 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e7 (77.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e6 (60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e18 (62.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e8 (72.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e26 (65.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eChest pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e2 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e4 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e4 (15.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e3 (60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e1 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e4 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e4 (15.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e1 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e3 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e1 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e4 (15.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eInsomnia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e1 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e2 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e3 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e3 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eBlood creatinine increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e1 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e2 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eDyspnea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e1 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e2 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eHypocalcemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e2 (40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e2 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eMedical device site pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e1 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e1 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e2 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e1 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e1 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e1 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e3 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003ePleural effusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e1 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e2 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003ePyrexia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e1 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e1 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e2 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eThrombosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e2 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eLegend.\u0026nbsp;\u003c/strong\u003ePercentages are based on number of subjects with TEAEs.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"respiratory-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"rere","sideBox":"Learn more about [Respiratory Research](http://respiratory-research.biomedcentral.com/)","snPcode":"12931","submissionUrl":"https://submission.nature.com/new-submission/12931/3","title":"Respiratory Research","twitterHandle":"@RespiratoryBMC","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Empyema, single chain urokinase plasminogen activator, fibrinolysis, intrapleural enzymatic therapy, complicated parapneumonic pleural effusions, nondraining pleural effusions, plasminogen activator inhibitor-1","lastPublishedDoi":"10.21203/rs.3.rs-9348224/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9348224/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eSingle 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\u003cstrong\u003e \u003c/strong\u003ewas a randomized, double-blind, placebo-controlled, multi-center, dose-ranging study in hospitalized subjects with infected, non-draining pleural effusions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eLTI-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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003e40/43 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\u0026lt;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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eNo 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration: \u003c/strong\u003eClinicalTrials.gov NCT04159831\u003cem\u003e. \u003c/em\u003eRegistration date: November 12, 2019\u003c/p\u003e","manuscriptTitle":"The LTI-01-2001 Phase 2 Trial of Intrapleural LTI-01 in Patients with Infected, Non- Draining Pleural Effusions","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-10 17:01:02","doi":"10.21203/rs.3.rs-9348224/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-14T13:32:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-13T21:32:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-11T21:49:26+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-04T19:01:30+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-29T12:41:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"298744856681441636108683478145579380791","date":"2026-04-21T16:43:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"111723025132728221215176703296734626871","date":"2026-04-19T19:59:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"62039003602704839161497404601367964785","date":"2026-04-14T19:29:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"218398726635530493792229992737478229593","date":"2026-04-14T12:05:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-14T11:50:58+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-09T23:30:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-09T10:04:25+00:00","index":"","fulltext":""},{"type":"submitted","content":"Respiratory Research","date":"2026-04-07T17:21:22+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"respiratory-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"rere","sideBox":"Learn more about [Respiratory Research](http://respiratory-research.biomedcentral.com/)","snPcode":"12931","submissionUrl":"https://submission.nature.com/new-submission/12931/3","title":"Respiratory Research","twitterHandle":"@RespiratoryBMC","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4c134357-92b5-4348-bc77-499314e1afda","owner":[],"postedDate":"April 10th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-14T13:32:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-13T21:32:19+00:00","index":21,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-11T21:49:26+00:00","index":20,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-04T19:01:30+00:00","index":19,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-14T13:39:54+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-10 17:01:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9348224","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9348224","identity":"rs-9348224","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}