Bone Marrow Mesenchymal Stem Cell Extracellular Vesicle Treatment of Respiratory Failure from COVID-19: Endpoint Analysis of Expanded Access Safety Trial

Bone Marrow Mesenchymal Stem Cell Extracellular Vesicle Treatment of Respiratory Failure from COVID-19: Endpoint Analysis of Expanded Access Safety Trial | 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 Short Report Bone Marrow Mesenchymal Stem Cell Extracellular Vesicle Treatment of Respiratory Failure from COVID-19: Endpoint Analysis of Expanded Access Safety Trial Vikram Sengupta, Sascha Qian, John Ransom, Sam Suzuki, David Park, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8890163/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract The safety of an extracellular vesicle (EV) enriched secretome from bone marrow mesenchymal stem cells (BM-MSCs) was evaluated in a multi-site, prospective, expanded access trial as potential treatment for respiratory failure due to COVID-19. Subjects (103) received up to three doses of 15 mL IP every 72 hours. The primary outcome was all cause 60-day mortality. Secondary outcomes included serious adverse events. One TEAE (grade 1 hyperpigmentation at the infusion site) related to IP occurred. 60-day mortality was 29% for all patients, 22.4% in patients <65 years and 41.7% in patients ≥65 years. Mean ventilation free days was 40.8 for all patients, 44.7 days in patients <65 years and 33.4 days in patients ≥65 years. Median time to hospital (IQR) discharge by Kaplan-Meier was 11 (5.0-NR) days in all patients, 9 (5.0-NR) days in patients <65 years and 19 (5.5-NR) days in patients ≥65 years. The IP (15 mL dose) is safe in patients with severe or critical COVID-19 respiratory failure. Extracellular vesicle bone marrow mesenchymal stem cell COVID-19 safety efficacy Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Following early observations of higher than expected mortality among intubated patients with severe COVID-19, many physicians expressed doubt that that the initial presentations were entirely consistent with “classic ARDS”.[ 1 ] Large observational studies suggest that, ultimately, hospitalized patients with persistent COVID-19 associated ARDS develop lung-mechanics similar to other sepsis-based ARDS and that COVID-19 associated ARDS pathology is highly similar to ARDS of any cause.[ 2 – 4 ] These patients accumulate inflammatory infiltrates in the lung parenchyma, oxidative stress from the high FiO 2 and mechanical microtrauma from positive pressure mechanical ventilation—all factors leading to diffuse alveolar damage, which is the most common histologic pattern identified in patients with ARDS.[ 5 ] Pathologic examination of patients with COVID-19 associated ARDS in Wuhan, China revealed alveolar epithelial injury, reactive hyperplasia of Type II pneumocytes, hyaline membrane formation, and fibroblastic plugs in the air-spaces, all indicative of how COVID-19 associated ARDS can rapidly devolve into a fatal state of minimal gas exchange.[ 6 ] Despite the ongoing investigations in COVID-19, the optimal management of acute respiratory distress syndrome (ARDS) morbidity remains ill-defined but increasingly critical and is in need of safe, new and effective therapeutic treatments. A recent meta-analysis indicates that mesenchymal stem cells (MSC) of different tissue origins can improve the short-term survival of ARDS patients.[ 7 ] However, randomized data has not found statistical significance in mortality due to COVID-19 related respiratory failure.[ 8 – 10 ] On the other hand, bone marrow mesenchymal stem cells (BM-MSC) have demonstrated signals of efficacy in several pulmonary conditions, including COVID-19.[ 8 , 11 – 13 ] Cell therapy is limited by scalability, distribution of product, and possible prothrombotic events.[ 14 – 16 ] The investigational product (IP) employed herein, ExoFlo ™ , is an advanced extracellular vesicle (EV) enriched secretome preparation in Phase 3 clinical trial for all-cause ARDS that is isolated from a single donor BM-MSC culture and conveys the anti-inflammatory, immunomodulatory, and regenerative properties of BM-MSC without these limitations of cellular therapy.[ 17 – 20 ] The IP’s promising efficacy and safety in COVID-19 patients has been demonstrated using up to two doses in both an early pandemic investigator initiated study of 24 patients and a randomized double blinded placebo controlled phase II clinical trial including 102 patients.[ 21 , 22 ] Both trials showed mortality benefit with the IP, especially in patients less than 65 years old who met criteria for acute respiratory distress syndrome (ARDS). To provide additional patient access to the novel technology during the COVID-19 pandemic emergency and to further evaluate the clinical safety and potential for efficacy of the IP for the treatment of hospitalized patients with respiratory failure from severe or critical COVID-19, regardless of severity of ARDS (mild, moderate, severe, need for ECMO), an expanded access clinical trial was initiated in multiple centers across the United States (NCT04657458). We herein describe the endpoint data results of this expanded access clinical trial in over 100 patients treated with up to three doses of 15 mL of IP. We hypothesized that the IP would be safe in the treatment of hospitalized COVID-19 patients, regardless of the severity of respiratory status. RESULTS Trial participants A total of 103 patients were enrolled and treated (Table 2). Patients were evenly balanced by gender and 35% were age 65 or above. A majority of patients were white (75%) despite efforts to be fully inclusionary, and the mean body mass index (BMI) was 34.1 (SD: 9.0). Screening exams were performed at a mean (SD) of 1.5 (0.56) days prior to the first infusion and ranged from 1 to 4 days. The mean time between COVID diagnosis and first infusion was 8.5 (7.8) days with a range of 1 to 50 days. Over 50% had received prior remdesivir treatment while 95% had received prior dexamethasone treatment. Of the 103, 11% were on mechanical ventilation at the time of first IP infusion. Many patients were maximized on high flow nasal cannula in an attempt to achieve non mechanical ventilatory oxygen support. However, many patients had comorbidities that increased the SOFA score regardless. Proportions of all treated subjects who received any amount of 1, 2, and 3 doses are 100%, 73%, and 51%, respectively (Online Resource Table 6). Median time from dose 1 to doses 2 and 3 are 2.9 days (Interquartile range (IQR): 2.80-3.04) and 6.0 days (5.84-6.03), respectively, indicating high compliance with the per-protocol dose schedule. Safety The Safety Analysis Data Set (Table 3) consisted of all 103 enrolled subjects who received any dose of IP. No AEs or SAEs caused a pause in patient recruitment or clinical trial discontinuation. No infusion reaction or AEs were within the first 72 hours. Treatment-Emergent Adverse Events (TEAEs) and serious TEAEs of any grade occurred, but only one TEAE was determined to be related to IP. This was hyperpigmentation that lasted 4-days at the infusion site and graded as a Grade 1. We investigated the relationship between safety events and the number of doses of IP received in the Safety Analysis Set. As shown in Online Resource Table 7, no exposure-response relationship amongst the percentages of patients experiencing Grade-3 or -4 safety events was observed. When the duration of hospitalization was controlled to those subjects who either died or were hospitalized until day 10, the percentage of subjects experiencing safety events are also evenly distributed among the three dosage groups (Online Resource Table 8). Efficacy Parameters The primary endpoint of overall mortality (OS) among all patients was 29% (Table 4). The 60-day mortality was 22% in patients <65 years and 42% in those ≥65 years (Table 5). Median time to death was not reached (NR) (Kaplan-Meier (KM), Figure 2A) and the KM mortality rate was 30.6% at 60 days for all treated patients; patients <65 years had an estimated mortality rate of 23.8% versus 43.1% in aged ≥65 years. Median (IQR) time to discharge calculated by KM method (Figure 2B) was 11 (5.0-NR) days overall; it was 9 days (5.0-NR) for 65 years. Mean (SD) of VFDs was 40.8 (25.4) days out of the 60-day follow-up overall (Table 4), and for patients <65 and ≥65 years it was 44.7 (24.1) and 33.4 (26.3) days, respectively (Table 5). The mean (SD) increase in PaO 2 /FiO 2 ratio from baseline to day 7 for the ITT population was 115 (125.2) mmHg (Table 4). Unlike the other metrics, the mean PaO 2 /FiO 2 increase over seven days was nearly identical between the two age groups, with those <65 achieving 116 mmHg improvement and the ≥65-year group achieving 114 mmHg (Table 5). Among 92 treated subjects who were not intubated at baseline, 19 (20.7%) subjects received mechanical ventilation (MV) with median (IQR) of 7 (3 -11) days to require MV. And these patients were on MV for a median duration of 9 (3 - 17) days. Exploratory Endpoints All four acute phase biomarkers declined steadily over the 61-day study with declines most pronounced from day 15 onwards (Online Resource Figure 3). The percentages of any grade TEAEs, TE SAEs or TEAEs that led to death were higher with 3 doses (Online Resource Table 7). DISCUSSION At endpoint of this prospective, expanded access trial it is demonstrated that a novel biological drug candidate based on BM-MSC EV technology and in advanced stages of development is safe in the treatment of hospitalized COVID-19 patients. There was only one Grade 1 TEAE related to IP throughout the duration of follow up for all 103 patients underscoring the safety profile in a critically ill patient population. The increased percentage of any grade TEAEs, TE SAEs and TEAEs that led to death in those receiving three doses as opposed to one or two doses was likely related to the fact that these subjects were still sick on Day 7 such that the increased any grade AEs reflected their longer hospitalization. This conclusion was supported by controlling the analysis to those subjects who died or remained hospitalized until day 10 and the observed even distribution of the subjects throughout the three dosage groups who experienced safety events. The lack of an exposure-response relationship regarding safety events in either analysis argues that safety of the IP is not affected up to 3-doses. These results further support that a novel technology with the potential for efficacy of intact stem cells and without the limitations of stem cells, such as the IP studied here, can be safely administered to seriously ill COVID-19 patients. All-cause 60-day mortality was 29.1%, consistent with the 15 mL IP treatment arms (29.4%) of our previously reported randomized, double blinded, placebo control phase 2 clinical trial (ClinicalTrials.gov Identifier: NCT04657458) where a significant mortality benefit was observed in COVID-19 patients with respiratory failure aged 18 to 65 years.[21] In the subgroup of patients aged 18 to 65, who showed better survival in moderate to severe ARDS in the phase 2 study, mortality was 22% as compared to 42% in patients aged ≥65 in this study. This may be due to a higher occurrence of co-morbidities seen in the aging population between age 65 to 85. Alternatively, younger patients may be better able to recover from the physiologic burden of ARDS/COVID-19. Although an age difference was not apparent for the PaO 2 /FiO 2 change from baseline, more VFDs and a more rapid time to discharge was evident for the age 18 to 65 population. These age-dependent differences in response to IP suggest there may be opportunity to improve outcomes for older patients by increasing the dose amount and/or frequency, a possibility to be evaluated in the current phase 3 RCT. Several other randomized clinical trials have been conducted to evaluate various small molecule drugs and biologic products for the treatment of COVID-19, all with conflicting results. In the phase 3 RCT of 1,114 patients randomized to remdesivir versus placebo, patients randomized to remdesivir had a shorter time to recovery, but there was no significant mortality benefit observed.[23] However, the RECOVERY trial (NCT04381936) found that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduced 28-day mortality in patients with COVID-19 requiring respiratory support. However, glucocortocoids carry significant well known risks.[24] Similarly, tocilizumab significantly improved 28-day survival and probability of discharge in COVID-19 patients.[25] Ivermectin has not shown a significant benefit when tested in thousands of COVID-19 patients either alone or in combination with metformin and fluvoxamine.[26, 27] The protease inhibitor combination drug Paxlovid (nirmatrelvir/ritonavir) has been effective at controlling COVID-19 disease progression, but strong CYP3A inhibition by the ritonavir component of Paxlovid results in drug-drug interaction complications for many patients taking commonly prescribed medications. Other approved small molecule drugs like remdesivir and molnupiravir also have limitations in terms of efficacy and adverse events such as potential drug-drug interactions, elevated liver enzymes and electrocardiogram abnormalities.[28-32] The ongoing significant threat of the SARS-CoV-2 virus and limitations of currently approved therapeutics and underlying technologies indicate that new and safe therapeutics are needed, particularly those with novel and safe mechanisms of action that are agnostic to new variants. Vaccine and biologic technologies have helped to reduce the surges in COVID-19 cases and deaths, but the potential for these numbers to again spike remains a threat due to the high mutability of the SARS-CoV-2 virus and potential for increasingly transmissible variants to emerge. The revocation of EUA approval for the monoclonal antibody bebtelovimab due to emergence of the BQ.1 and BQ.1.1 SARS-CoV-2 variants that are not recognized by bebtelovimab illustrates the ongoing challenge of developing monoclonal antibody drugs quickly enough to outpace the rapid mutation rate of the virus. When bone marrow derived mesenchymal stem cells (MSCs) were studied in randomized clinical trials, safety was highlighted but significant benefits in mortality were not seen.[8] EVs from MSC offer a safe and effective means of scaling MSC therapy to deliver higher, consistent doses without cell death from the cryorecovery process observed with MSC therapy. EVs are a natural product that play important cell-cell communication roles in daily physiology and play key roles in times of stress. The IP is a bone marrow derived enriched EV secretome product that contains many different classes of biomolecules capable of modifying cell function such as chemokines, cytokines, growth factors and RNA species capable of immunomodulatory and regenerative activity. The EVs may act through multiple mechanisms of action to direct the regenerative and anti-inflammatory processes of the BM-MSC from which they are derived.[33, 34] While this study was not designed to prove efficacy or mechanism, the reduction of all four measured markers of systemic inflammation is consistent with a potential immunomodulatory effect of the IP (Online Resource Figure 3) and further study of this potential mechanism will be pursued. This secretome based therapeutic approach bypasses the challenges of direct allogeneic or autologous viable BM-MSC transplantation.[17, 35] EVs easily pass through capillaries, making them a safer option for intravenous administration in contrast to cellular therapies. The IP is not subject to cell therapy associated issues of viability and unregulatable shifts in potency and efficacy profiles once delivered into the patient. As shown here and in previous studies, the IP is extremely safe when administered intravenously. In addition, the trial herein is the first to show an EV product with potential survival benefit that, in phase 3, may prove superior to the clinical trial results from the aforementioned therapeutic candidates. While this represents the largest expanded access program using an EV product for COVID-19, there are limitations to this study. First, there is no comparison group with placebo or variable dosing to understand the true efficacy benefit. Nor does the study address the optimal dose or dosing interval or the safety of such optimal protocols. Second, the protocol enrolled a broad range of respiratory failure including patients on noninvasive respiratory support to those on invasive respiratory support with mechanical ventilation. Third, while all included patients met criteria for moderate to severe ARDS, the protocol was not written to compare efficacy between patient phenotype, or ARDS phenotype. Last, it is unclear at this time why the IP appears to have a greater impact in a younger patient cohort. Given the preliminary results demonstrated by the IP, the FDA issued a regenerative medicine advanced therapeutic (RMAT) designation to facilitate a faster time to approval of the IP for treatment of severe or critical confirmed COVID-19. A BM-MSC EV enriched secretome product that is manufactured to consistent quality standards represents a novel, safe therapeutic candidate with potential for the treatment of COVID-19 induced and all-cause ARDS, and this potential is currently being fully evaluated with the IP in a Phase 3 clinical trial (NCT05354141). EXPERIMENTAL PROCEDURES Design A prospective, multi-center, expanded access trial was conducted. Enrollment for DB-EF-EXPANDEDACCESS-001 began in December 2020 and reached midpoint in December of 2022. Five clinical trial sites in the United States actively participated in patient recruitment and enrollment under IND 21669. Patients with severe or critical COVID-19 who met modified Berlin criteria for acute respiratory distress syndrome (ARDS) as defined by onset of symptoms within one week of insult, respiratory failure not fully explained by cardiac failure or fluid overload, PaO 2 /FiO 2 £ 200, PEEP >5 cm H2O, and bilateral opacities not fully explained by effusions or lung collapse were offered enrollment (Table 1).[36] See Figure 1 for CONSORT diagram for patient screening and enrollment. We support inclusive, diverse, and equitable conduct of research. Each lot of the IP meets stringent release specifications, including proteomic, mRNA and miRNA characterization as previously described in greater detail.[37] Briefly, the IP is manufactured per FDA guidance for Current Good Manufacturing Practices (cGMP) with all manufacturing processes controlled under a Quality Management System, and implementation of lot-specific master batch records and specified release criteria for each lot of IP. The size and quantity of EVs and the presence of a specific surface marker expression profile are confirmed. Identity assays are combined with validated potency assays to demonstrate the mechanism of action is functional. A 15 mL dose provides 1.2 x 10 12 EV particles. Patients (n=103) were enrolled in the open label prospective DB-EF-EXPANDEDACCESS-001. After informed consent, patients received a 100 mL intravenous infusion over 60 minutes: 15 mL IP with 85 mL NS. A repeat of the same study treatment occurred on Day 4 and Day 7 if the patient had not recovered (SpO 2 ≥93% on room air or PaO 2 /FiO 2 ≥300 mmHg). All patients were followed for 60 days, or until hospital discharge or death. The trial protocol was approved by the institutional review board (IRB) at each site (or a centralized IRB as applicable) and overseen by an independent data and safety monitoring board (DSMB). Written informed consent (or consent by other IRB-approved process) was obtained from each patient or patient’s legally authorized representative if the patient was unable to provide consent. Objectives and Outcomes The primary endpoint was all-cause 60-day binomial mortality. Secondary endpoints included 1) treatment-emergent SAEs defined as any SAEs starting on or after the first dose date up to 30 days after the last dose, 2) ventilation-free days (VFDs) within the first 60-day follow-up, and 3) time to hospital discharge. Exploratory outcome measurements for acute phase reactants including CRP, D-dimer and ferritin and immune cell subset counts measured up to Day 61, Sequential Organ Failure Assessment (SOFA) scores measured as change from baseline to Day 15, and PaO 2 /FiO 2 change from baseline to Day 7. Measures Patients were assessed daily from Day 1 to Day 60 during hospitalization. All treatment emergent adverse events (TEAEs), serious adverse events (SAEs) and grade 3 or 4 adverse events (AEs) representing increased severity from Day 1, and any grade suspected drug-related hypersensitivity reactions were recorded. Statistical Analysis The data underlying this article are available in this article. This study used all treated participants who received at least a partial dose of the IP treatment regimen for efficacy and safety endpoints. Pre-defined sub-group analysis of 60-day all-cause mortality was performed on age groups, to investigate whether treatment with IP had more of an effect on outcome in specific patient groups.[21] Missing data was not imputed, and the results were summarized based on available data. Abbreviations ARDS Acute respiratory distress syndrome BM-MSC Bone marrow mesenchymal stem cell EV Extracellular vesicle IQR Interquartile range PEEP Positive end expiratory pressure SAE Serious adverse event SOFA Sequential organ failure assessment TEAE Treatment emergent adverse event Declarations Funding: Sponsors (Direct Biologics, LLC) funded the study, provided ExoFlo, interpreted the data and drafted the manuscript. Conflicts of interest: Timothy A. Moseley: CSO at Direct Biologics, John T. Ransom: Sr. Medical Writer at Direct Biologics, Sascha Qian: prior Associate CMO at Direct Biologics, Vikram Sengupta: prior CMO at Direct Biologics Ethics Approval: The trial protocol was approved by the institutional review board (IRB) at each site (or a centralized IRB as applicable) and overseen by a data and safety monitoring board (DSMB) that was fully independent of both study sponsor and director. Consent to Participate: Written informed consent (or consent by other IRB-approved process) was obtained from each patient, or patient’s legally authorized representative if the patient was unable to provide consent, following a discussion of informed consent principles with the investigator. Consent for Publication: Consent for publication is contained within the informed consent form and permission is granted upon signing the consent form. Availability of Data and Material: Additional data may be made available upon reasonable request to the corresponding author. Code Availability : Not applicable Author Contributions: VS: protocol design, interpretation of data, editing manuscript; SQ: protocol design, interpretation of data, editing manuscript; JTR: protocol design, interpretation of data, editing manuscript; SS: protocol design, interpretation of data, editing manuscript; DJP: enrollment of patients, protocol design, editing manuscript; TIM: enrollment of patients, protocol design, editing manuscript; BPW: enrollment of patients, protocol design, editing manuscript; JJW: enrollment of patients, protocol design, editing manuscript; MA: enrollment of patients, protocol design, editing manuscript; JMM: enrollment of patients, protocol design, editing manuscript; TAM: protocol design, drafting and finalizing manuscript. References Li, X., & Ma, X. (2020). Acute respiratory failure in COVID-19: is it typical ARDS? Critical care (London England) , 24 (1), 198. Fan, E., Beitler, J. R., Brochard, L., et al. (2020). 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W., Fang, X., Krasnodembskaya, A., Howard, J. P., & Matthay, M. A. (2011). Concise review: Mesenchymal stem cells for acute lung injury: role of paracrine soluble factors. Stem Cells , 29 (6), 913–919. Yu, B., Zhang, X., & Li, X. (2014). Exosomes derived from mesenchymal stem cells. International journal of molecular sciences , 15 (3), 4142–4157. Riviello, E. D., Kiviri, W., Twagirumugabe, T., et al. (2016). Hospital Incidence and Outcomes of the Acute Respiratory Distress Syndrome Using the Kigali Modification of the Berlin Definition. American journal of respiratory and critical care medicine , 193 (1), 52–59. Sengupta, V., Sengupta, S., Lazo, A. Jr., Hicok, K. C., Moseley, T., Response to, Lim (2020). re: Exosomes Derived from Bone Marrow Mesenchymal Stem Cells as Treatment for Severe COVID-19. Stem cells and development 29(14), 879–881. Tables Table 1. Inclusion and Exclusion Criteria Inclusion Criteria: Provision of informed consent by self or proxy. Stated willingness to comply with study protocol. Male or female of any age ≥ 18 years of age May be pregnant unless the patient has one or more conditions listed under Exclusion Criteria #4. Positive Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) SARS-CoV-2. Moderate to severe ARDS as defined by timing within 1 week of known clinical insult or new or worsening respiratory symptoms, bilateral opacities not fully explained by effusions or lung collapse, and respiratory failure not fully explained by cardiac failure or fluid overload, and PaO 2 /FiO 2 £ 200 mmHg. Acute presentation of hypoxic respiratory failure requiring noninvasive oxygen support OR mechanical ventilation (MV). Agreement to use highly effective birth control contraception if of reproductive age and potential. Exclusion Criteria: Active malignancy requiring treatment within the last five years. Eligibility for enrollment in Protocol DB-EF-PhaseII-001. Patients who are not full code. Pregnant patients with current or past history of eclampsia, preeclampsia, hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome during pregnancy. New York Heart Association (NYHA) Functional Class III (symptoms present during ordinary activities) or IV Heart Failure (symptoms present at rest) or listed for heart transplant. Chronic Kidney Disease (CKD) Stage IV (GFR 15-29 mL/min/1.73m 2 ) and Stage V (GFR < 15 mL/min/1.73m 2 ) or listed for kidney transplant. Hepatic Impairment with Model for End-Stage Liver Disease (MELD) score ≥ 30 or listed for liver transplant. Patients on Extracorporeal Membrane Oxygenation. Table 2. Demographics and Baseline Characteristics (Safety Analysis Set). Demographics and Baseline Characteristics Statistics (IP 15 mL up to 3 Doses) (N=103) Age n 103 Mean (SD) 56.7 (16.42) Min, Max 22, 90 Age ≥ 65 n (%) 36 (35.0) Age < 65 n (%) 67 (65.0) Gender Male n (%) 58 (56.3) Female n (%) 45 (43.7) Race American Indian or Alaska Native n (%) 0 Asian n (%) 8 (7.8) Black or African American n (%) 13 (12.6) Native Hawaiian or Other Pacific Islander n (%) 0 White n (%) 77 (74.8) Unknown or Other n (%) 5 (4.9) BMI (kg/m 2 ) a n 102 Mean (SD) 34.147 (8.9523) Min, Max 18.16, 66.76 Respiratory Rate (breaths/min) a n 103 Mean (SD) 25.0 (7.23) Min, Max 11, 46 Time from the First Covid-19 Diagnosis to First IP Dose Date (days) n 103 Mean (SD) 8.5 (7.80) Min, Max 1, 50 Time from Screening Visit to First IP Dose Date (days) n 103 Mean (SD) 1.5 (0.56) Min, Max 1, 4 Total SOFA Score a n 103 Mean (SD) 3.2 (1.96) Min, Max 2, 12 P/F Ratio (mmHg) a n 99 Mean (SD) 118.454 (50.9406) Min, Max 45, 245 Prior Therapy b n 98 Remdesivir n (%) 57 (55.3) Plasma n (%) 0 Dexamethasone n (%) 98 (95.1) Mechanical Ventilation Intubated n (%) 11 (10.7) Non-Intubated c n (%) 92 (89.3) Intubated (MV) on Study n 19 Time on Intubation (MV) (days) Median 9.0 (1 st , 3 rd Quartiles) (3.0, 17.0) Min, Max 1, 37 a Baseline is the last measure prior to the first dose of IP (Day 0 or Day 1 5 min before dosing). b If the agent started prior to the first dose of IP regardless of its end date. c All patients that were not intubated were on non-invasive ventilation of BiPAP or CPAP with a minimum of 5L 02/min Table 3. Overall Summary of Safety (Safety Analysis Set) Safety Parameter (IP 15 mL up to 3 Doses) (N=103) n (%) Any TEAEs a Any Grade 76 (73.8) Grade 3 or 4 14 (13.6) Serious TEAEs a Any Grade 41 (39.8) Grade 3 or 4 13 (12.6) IP-Related TEAEs 1 (1.0) IP-Related Serious TEAEs 0 TEAEs That Led to Dose Interruption 2 (1.9) TEAEs That Led to Missing Dose or Discontinued the Treatment Early 1 (1.0) TEAEs That Led to Death 28 (27.2) IP Infusion Reaction 0 TEAE = Treatment-Emergent Adverse Events, are defined as any adverse event that started between the first dose date and 30 days post the last dose date, inclusively. a Toxicity grades of adverse events are evaluated based on criteria of NCI-CTCAE v5.0. Each subject is counted once to the worst grade at subject-level. Note: Related = Definitely, Probably, or Potentially Related. Table 4. Summary of Efficacy (Full Analysis Set). Study Endpoints Statistics (IP 15 mL up to 3 Doses) (N=103) Subjects Who Discharged from Hospital n (%) 68 (66.0) Time to Discharge (KM) Median 11.0 days (1st, 3rd Quartiles) (5.0, NR) Mean Time to Discharge (Restricted to Discharged Subjects) n 68 Mean (SD) 9.9 days (10.53) Min, Max 1, 47 Subjects Who Died Within 30 Days n (%) 27 (26.2) Subjects Who Died Within 60 Days n (%) 30 (29.1) 95% CI (exact) 20.6, 38.9 Median Time to Death (KM) Median NR Mortality Rate at 15 Days (KM) % (95% CI) 19.1 (12.6, 28.3) Mortality Rate at 30 Days (KM) % (95% CI) 27.3 (19.6, 37.3) Mortality Rate at 60 Days (KM) % (95% CI) 30.6 (22.5, 40.8) Mean Time to Death (Restricted to Subjects Who Died) n 30 Mean (SD) 16.2 days (12.14) Min, Max 6, 50 a PaO 2 /FiO 2 Ratio Increase from Baseline to Day 7 (mmHg) n 97 Mean (SD) 115.149 (125.2062) Min, Max 0, 617.11 b Ventilation-Free Days (within 60 Days) n 103 Mean (SD) 40.8 (25.36) Min, Max 0, 61 Day 15 SOFA Score Change from Baseline n 29 Mean (SD) 1.2 (4.24) Min, Max -6, 9 Day 29 SOFA Score Change from Baseline n 16 Mean (SD) -0.6 (3.42) Min, Max -6, 7 KM = Kaplan Meier method, NR = Not Reached. a PaO 2 /FiO 2 ratio: All treated subjects with baseline and at least one PaO 2 /FiO 2 ratio measured at Day 4 or 7. For missing Day 7 data, 380 mmHg was assigned for discharged patients, and no change (0) was assigned to patients with negative change from the baseline or died before Day 7. b Ventilation-free days: days when patients are not on mechanical ventilation within 60 days of follow-up. Table 5. Summary of Efficacy by Age Group (Full Analysis Set) Study Endpoints Statistics Age ≥ 65 (N=36) Age < 65 (N=67) Subjects Who Discharged from Hospital n (%) 20 (55.6) 48 (71.6) Time to Discharge (KM) Median 19.0 days 9.0 days (1st, 3rd Quartiles) (5.5, NR) (5.0, NR) Mean Time to Discharge (Restricted to Discharged Subjects) n 20 48 Mean (SD) 10.0 days (10.80) 9.8 days (10.53) Min, Max 3, 47 1, 44 Subjects Who Died Within 30 Days n (%) 15 (41.7) 12 (17.9) Subjects Who Died Within 60 Days n (%) 15 (41.7) 15 (22.4) 95% CI (exact) 25.5, 59.2 13.1, 34.2 Median Time to Death (KM) Median NR NR Mortality Rate at 15 Days (KM) % (95% CI) 37.1 (23.5, 55.3) 9.4 (4.3, 19.6) Mortality Rate at 30 Days (KM) % (95% CI) 43.1 (28.6, 61.1) 18.8 (11.1, 30.7) Mortality Rate at 60 Days (KM) % (95% CI) 43.1 (28.6, 61.1) 23.8 (15.1, 36.3) Mean Time to Death (Restricted to Subjects Who Died) n 15 15 Mean (SD) 10.5 days (5.11) 21.9 days (14.51) Min, Max 6, 25 7, 50 a PaO 2 /FiO 2 Ratio Increase from Baseline to Day 7 (mmHg) n 34 63 Mean (SD) 114.028 (124.0509) 115.754 (126.8134) Min, Max 0, 396.43 0, 617.11 b Ventilation-Free Days (within 60 Days) n 36 67 Mean (SD) 33.4 (26.26) 44.7 (24.14) Min, Max 0, 61 0, 61 Day 15 SOFA Score Change from Baseline n 7 22 Mean (SD) -2.0 (2.94) 2.2 (4.12) Min, Max -6, 3 -6, 9 Day 29 SOFA Score Change from Baseline n 4 12 Mean (SD) -3.5 (2.65) 0.4 (3.15) Min, Max -6, 0 -3, 7 KM = Kaplan Meier method, NR = Not Reached. a PaO 2 /FiO 2 ratio: All treated subjects with baseline and at least one PaO 2 /FiO 2 ratio measured at Day 4 or 7. For missing Day 7 data, 380 mmHg was assigned for discharged patients, and no change (0) was assigned to patients with negative change from the baseline or died before Day 7. b Ventilation-free days: days when patients are not on mechanical ventilation within 60 days of follow-up. Additional Declarations Competing interest reported. Vikram Sengupta: prior CMO at Direct Biologics, Sascha Qian: prior Associate CMO at Direct Biologics, John T. Ransom: Sr. Medical Writer at Direct Biologics, Timothy A. Moseley: CSO at Direct Biologics Supplementary Files SupplementaryInformation.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 28 Feb, 2026 Reviews received at journal 26 Feb, 2026 Reviews received at journal 20 Feb, 2026 Reviewers agreed at journal 19 Feb, 2026 Reviewers agreed at journal 19 Feb, 2026 Reviewers agreed at journal 19 Feb, 2026 Reviewers agreed at journal 18 Feb, 2026 Reviewers invited by journal 18 Feb, 2026 Editor assigned by journal 17 Feb, 2026 Submission checks completed at journal 17 Feb, 2026 First submitted to journal 16 Feb, 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. 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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-8890163","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":593777831,"identity":"d5d0f114-a492-4ccc-979d-17b9e11a024d","order_by":0,"name":"Vikram Sengupta","email":"","orcid":"","institution":"Direct Biologics","correspondingAuthor":false,"prefix":"","firstName":"Vikram","middleName":"","lastName":"Sengupta","suffix":""},{"id":593777833,"identity":"b16f8e6c-364b-4c17-93aa-9cf67e39d68f","order_by":1,"name":"Sascha Qian","email":"","orcid":"","institution":"Direct Biologics","correspondingAuthor":false,"prefix":"","firstName":"Sascha","middleName":"","lastName":"Qian","suffix":""},{"id":593777834,"identity":"6b25790f-c50e-4954-a5b8-3e94dd0fe7b6","order_by":2,"name":"John Ransom","email":"","orcid":"","institution":"Direct Biologics","correspondingAuthor":false,"prefix":"","firstName":"John","middleName":"","lastName":"Ransom","suffix":""},{"id":593777835,"identity":"d471540a-3d00-43df-8110-92dc610c7fe0","order_by":3,"name":"Sam Suzuki","email":"","orcid":"","institution":"Direct Biologics","correspondingAuthor":false,"prefix":"","firstName":"Sam","middleName":"","lastName":"Suzuki","suffix":""},{"id":593777836,"identity":"5832af94-25c7-404d-9391-d3760d9ecce3","order_by":4,"name":"David Park","email":"","orcid":"","institution":"Providence St. Jude Medical 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Foundation","correspondingAuthor":false,"prefix":"","firstName":"James","middleName":"","lastName":"Walsh","suffix":""},{"id":593777841,"identity":"630cc145-8ce8-46b8-ac39-d417ac81cabd","order_by":8,"name":"Mustafa Awili","email":"","orcid":"","institution":"PRX Research","correspondingAuthor":false,"prefix":"","firstName":"Mustafa","middleName":"","lastName":"Awili","suffix":""},{"id":593777842,"identity":"fe679cbd-b53c-40c1-b5cb-ffebad36759c","order_by":9,"name":"Jack Mann","email":"","orcid":"","institution":"New York–Presbyterian Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jack","middleName":"","lastName":"Mann","suffix":""},{"id":593777843,"identity":"81f1ac80-47f8-4d8e-85b9-edecff9a2007","order_by":10,"name":"Timothy Moseley","email":"data:image/png;base64,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","orcid":"","institution":"Direct Biologics","correspondingAuthor":true,"prefix":"","firstName":"Timothy","middleName":"","lastName":"Moseley","suffix":""}],"badges":[],"createdAt":"2026-02-16 06:23:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8890163/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8890163/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103179230,"identity":"a36611eb-2c7b-4d26-84ab-cbec9209b62b","added_by":"auto","created_at":"2026-02-22 17:09:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":18401,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT Diagram.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8890163/v1/36cc6e735bf1053a05400c60.png"},{"id":103179247,"identity":"1b26f6d7-5134-401e-813b-a79d5d8632e9","added_by":"auto","created_at":"2026-02-22 17:09:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":55702,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier Plots. (a) Time to Death. NR = Not Reached. Time to Death is the interval in days from first dose of IP to subject's death. The interval is censored to study discontinuation or completion if the subject is alive. (b) Time to Discharge (Full Analysis Set). Time to Discharge is the interval in days from first dose of IP to discharge from hospital. The interval is censored to 60 days if the subject was not discharged.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8890163/v1/79b4f904b9bb41b7ec09d16b.png"},{"id":103179239,"identity":"fb74f06a-2992-4808-80c0-9700bf34eb41","added_by":"auto","created_at":"2026-02-22 17:09:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":664282,"visible":true,"origin":"","legend":"\u003cp\u003eGraphical Overview\u003c/p\u003e","description":"","filename":"GraphicalOverview.png","url":"https://assets-eu.researchsquare.com/files/rs-8890163/v1/887adfaded8cdc426f3083f2.png"},{"id":103504918,"identity":"5c031cc5-b43d-4050-9788-d1d5a74d56f2","added_by":"auto","created_at":"2026-02-26 13:22:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1719165,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8890163/v1/8a23ad17-1e14-43ad-9234-3f1db1164099.pdf"},{"id":103179257,"identity":"8d556c32-d8b8-4713-a4d2-e982745b6ede","added_by":"auto","created_at":"2026-02-22 17:09:38","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":30766,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-8890163/v1/a08b545ae4d1b57321ffe10a.docx"}],"financialInterests":"Competing interest reported. Vikram Sengupta: prior CMO at Direct Biologics, Sascha Qian: prior Associate CMO at Direct Biologics, John T. Ransom: Sr. Medical Writer at Direct Biologics, Timothy A. Moseley: CSO at Direct Biologics","formattedTitle":"Bone Marrow Mesenchymal Stem Cell Extracellular Vesicle Treatment of Respiratory Failure from COVID-19: Endpoint Analysis of Expanded Access Safety Trial","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eFollowing early observations of higher than expected mortality among intubated patients with severe COVID-19, many physicians expressed doubt that that the initial presentations were entirely consistent with \u0026ldquo;classic ARDS\u0026rdquo;.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] Large observational studies suggest that, ultimately, hospitalized patients with persistent COVID-19 associated ARDS develop lung-mechanics similar to other sepsis-based ARDS and that COVID-19 associated ARDS pathology is highly similar to ARDS of any cause.[\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] These patients accumulate inflammatory infiltrates in the lung parenchyma, oxidative stress from the high FiO\u003csub\u003e2\u003c/sub\u003e and mechanical microtrauma from positive pressure mechanical ventilation\u0026mdash;all factors leading to diffuse alveolar damage, which is the most common histologic pattern identified in patients with ARDS.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] Pathologic examination of patients with COVID-19 associated ARDS in Wuhan, China revealed alveolar epithelial injury, reactive hyperplasia of Type II pneumocytes, hyaline membrane formation, and fibroblastic plugs in the air-spaces, all indicative of how COVID-19 associated ARDS can rapidly devolve into a fatal state of minimal gas exchange.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] Despite the ongoing investigations in COVID-19, the optimal management of acute respiratory distress syndrome (ARDS) morbidity remains ill-defined but increasingly critical and is in need of safe, new and effective therapeutic treatments.\u003c/p\u003e \u003cp\u003eA recent meta-analysis indicates that mesenchymal stem cells (MSC) of different tissue origins can improve the short-term survival of ARDS patients.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] However, randomized data has not found statistical significance in mortality due to COVID-19 related respiratory failure.[\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] On the other hand, bone marrow mesenchymal stem cells (BM-MSC) have demonstrated signals of efficacy in several pulmonary conditions, including COVID-19.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] Cell therapy is limited by scalability, distribution of product, and possible prothrombotic events.[\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] The investigational product (IP) employed herein, ExoFlo\u003csup\u003e\u0026trade;\u003c/sup\u003e, is an advanced extracellular vesicle (EV) enriched secretome preparation in Phase 3 clinical trial for all-cause ARDS that is isolated from a single donor BM-MSC culture and conveys the anti-inflammatory, immunomodulatory, and regenerative properties of BM-MSC without these limitations of cellular therapy.[\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] The IP\u0026rsquo;s promising efficacy and safety in COVID-19 patients has been demonstrated using up to two doses in both an early pandemic investigator initiated study of 24 patients and a randomized double blinded placebo controlled phase II clinical trial including 102 patients.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] Both trials showed mortality benefit with the IP, especially in patients less than 65 years old who met criteria for acute respiratory distress syndrome (ARDS).\u003c/p\u003e \u003cp\u003eTo provide additional patient access to the novel technology during the COVID-19 pandemic emergency and to further evaluate the clinical safety and potential for efficacy of the IP for the treatment of hospitalized patients with respiratory failure from severe or critical COVID-19, regardless of severity of ARDS (mild, moderate, severe, need for ECMO), an expanded access clinical trial was initiated in multiple centers across the United States (NCT04657458). We herein describe the endpoint data results of this expanded access clinical trial in over 100 patients treated with up to three doses of 15 mL of IP. We hypothesized that the IP would be safe in the treatment of hospitalized COVID-19 patients, regardless of the severity of respiratory status.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003e\u003cu\u003eTrial participants\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 103 patients were enrolled and treated (Table 2). Patients were evenly balanced by gender and 35% were age 65 or above. A majority of patients were white (75%) despite efforts to be fully inclusionary, and the mean body mass index (BMI) was 34.1 (SD: 9.0). Screening exams were performed at a mean (SD) of 1.5 (0.56) days prior to the first infusion and ranged from 1 to 4 days. The mean time between COVID diagnosis and first infusion was 8.5 (7.8) days with a range of 1 to 50 days. Over 50% had received prior remdesivir treatment while 95% had received prior dexamethasone treatment. Of the 103, 11% were on mechanical ventilation at the time of first IP infusion. Many patients were maximized on high flow nasal cannula in an attempt to achieve non mechanical ventilatory oxygen support. However, many patients had comorbidities that increased the SOFA score regardless. Proportions of all treated subjects who received any amount of 1, 2, and 3 doses are 100%, 73%, and 51%, respectively (Online Resource Table 6). Median time from dose 1 to doses 2 and 3 are 2.9 days (Interquartile range (IQR): 2.80-3.04) and 6.0 days (5.84-6.03), respectively, indicating high compliance with the per-protocol dose schedule.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eSafety\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Safety Analysis Data Set (Table 3) consisted of all 103 enrolled subjects who received any dose of IP. No AEs or SAEs caused a pause in patient recruitment or clinical trial discontinuation. No infusion reaction or AEs were within the first 72 hours. Treatment-Emergent Adverse Events (TEAEs) and serious TEAEs of any grade occurred, but only one TEAE was determined to be related to IP. This was hyperpigmentation that lasted 4-days at the infusion site and graded as a Grade 1.\u003c/p\u003e\n\u003cp\u003eWe investigated the relationship between safety events and the number of doses of IP received in the Safety Analysis Set. As shown in Online Resource Table 7, no exposure-response relationship amongst the percentages of patients experiencing Grade-3 or -4 safety events was observed. When the duration of hospitalization was controlled to those subjects who either died or were hospitalized until day 10, the percentage of subjects experiencing safety events are also evenly distributed among the three dosage groups (Online Resource Table 8).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eEfficacy Parameters\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint of overall mortality (OS) among all patients was 29% (Table 4). The 60-day mortality was 22% in patients \u0026lt;65 years and 42% in those \u0026ge;65 years (Table 5). Median time to death was not reached (NR) (Kaplan-Meier (KM), Figure 2A) and the KM mortality rate was 30.6% at 60 days for all treated patients; patients \u0026lt;65 years had an estimated mortality rate of 23.8% versus 43.1% in aged \u0026ge;65 years. Median (IQR) time to discharge calculated by KM method (Figure 2B) was 11 (5.0-NR) days overall; it was 9 days (5.0-NR) for \u0026lt;65 and 19 days (5.5-NR) for \u0026gt;65 years.\u003c/p\u003e\n\u003cp\u003eMean (SD) of VFDs was 40.8 (25.4) days out of the 60-day follow-up overall (Table 4), and for patients \u0026lt;65 and \u0026ge;65 years it was 44.7 (24.1) and 33.4 (26.3) days, respectively (Table 5). The mean (SD) increase in PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e ratio from baseline to day 7 for the ITT population was 115 (125.2) mmHg (Table 4). Unlike the other metrics, the mean PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e increase over seven days was nearly identical between the two age groups, with those \u0026lt;65 achieving 116 mmHg improvement and the \u0026ge;65-year group achieving 114 mmHg (Table 5).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong 92 treated subjects who were not intubated at baseline, 19 (20.7%) subjects received mechanical ventilation (MV) with median (IQR) of 7 (3 -11) days to require MV. And these patients were on MV for a median duration of 9 (3 - 17) days.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eExploratory Endpoints\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll four acute phase biomarkers declined steadily over the 61-day study with declines most pronounced from day 15 onwards (Online Resource Figure 3). The percentages of any grade TEAEs, TE SAEs or TEAEs that led to death were higher with 3 doses (Online Resource Table 7).\u0026nbsp;\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eAt endpoint of this prospective, expanded access trial it is demonstrated that a novel biological drug candidate based on BM-MSC EV technology and in advanced stages of development is safe in the treatment of hospitalized COVID-19 patients. There was only one Grade 1 TEAE related to IP throughout the duration of follow up for all 103 patients underscoring the safety profile in a critically ill patient population. The increased percentage of any grade TEAEs, TE SAEs and TEAEs that led to death in those receiving three doses as opposed to one or two doses was likely related to the fact that these subjects were still sick on Day 7 such that the increased any grade AEs reflected their longer hospitalization. This conclusion was supported by controlling the analysis to those subjects who died or remained hospitalized until day 10 and the observed even distribution of the subjects throughout the three dosage groups who experienced safety events. The lack of an exposure-response relationship regarding safety events in either analysis argues that safety of the IP is not affected up to 3-doses. These results further support that a novel technology with the potential for efficacy of intact stem cells and without the limitations of stem cells, such as the IP studied here, can be safely administered to seriously ill COVID-19 patients.\u003c/p\u003e\n\u003cp\u003eAll-cause 60-day mortality was 29.1%, consistent with the 15 mL IP treatment arms (29.4%) of our previously reported randomized, double blinded, placebo control phase 2 clinical trial (ClinicalTrials.gov Identifier: NCT04657458) where a significant mortality benefit was observed in COVID-19 patients with respiratory failure aged 18 to 65 years.[21] \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the subgroup of patients aged 18 to 65, who showed better survival in moderate to severe ARDS in the phase 2 study, mortality was 22% as compared to 42% in patients aged \u0026ge;65 in this study. This may be due to a higher occurrence of co-morbidities seen in the aging population between age 65 to 85. Alternatively, younger patients may be better able to recover from the physiologic burden of ARDS/COVID-19. Although an age difference was not apparent for the PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e change from baseline, more VFDs and a more rapid time to discharge was evident for the age 18 to 65 population. These age-dependent differences in response to IP suggest there may be opportunity to improve outcomes for older patients by increasing the dose amount and/or frequency, a possibility to be evaluated in the current phase 3 RCT.\u003c/p\u003e\n\u003cp\u003eSeveral other randomized clinical trials have been conducted to evaluate various small molecule drugs and biologic products for the treatment of COVID-19, all with conflicting results. In the phase 3 RCT of 1,114 patients randomized to remdesivir versus placebo, patients randomized to remdesivir had a shorter time to recovery, but there was no significant mortality benefit observed.[23]\u003csub\u003e\u0026nbsp;\u003c/sub\u003eHowever, the RECOVERY trial (NCT04381936) found that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduced 28-day mortality in patients with COVID-19 requiring respiratory support. However, glucocortocoids carry significant well known risks.[24] Similarly, tocilizumab significantly improved 28-day survival and probability of discharge in COVID-19 patients.[25] Ivermectin has not shown a significant benefit when tested in thousands of COVID-19 patients either alone or in combination with metformin and fluvoxamine.[26, 27] The protease inhibitor combination drug Paxlovid (nirmatrelvir/ritonavir) has been effective at controlling COVID-19 disease progression, but strong CYP3A inhibition by the ritonavir component of Paxlovid results in drug-drug interaction complications for many patients taking commonly prescribed medications. Other approved small molecule drugs like remdesivir and molnupiravir also have limitations in terms of efficacy and adverse events such as potential drug-drug interactions, elevated liver enzymes and electrocardiogram abnormalities.[28-32] The ongoing significant threat of the SARS-CoV-2 virus and limitations of currently approved therapeutics and underlying technologies indicate that new and safe therapeutics are needed, particularly those with novel and safe mechanisms of action that are agnostic to new variants.\u003c/p\u003e\n\u003cp\u003eVaccine and biologic technologies have helped to reduce the surges in COVID-19 cases and deaths, but the potential for these numbers to again spike remains a threat due to the high mutability of the SARS-CoV-2 virus and potential for increasingly transmissible variants to emerge. The revocation of EUA approval for the monoclonal antibody bebtelovimab due to emergence of the BQ.1 and BQ.1.1 SARS-CoV-2 variants that are not recognized by bebtelovimab illustrates the ongoing challenge of developing monoclonal antibody drugs quickly enough to outpace the rapid mutation rate of the virus.\u0026nbsp;When bone marrow derived mesenchymal stem cells (MSCs) were studied in randomized clinical trials, safety was highlighted but significant benefits in mortality were not seen.[8] EVs from MSC offer a safe and effective means of scaling MSC therapy to deliver higher, consistent doses without cell death from the cryorecovery process observed with MSC therapy.\u0026nbsp;EVs are a natural product that play important cell-cell communication roles in daily physiology and play key roles in times of stress. The IP is a bone marrow derived enriched EV secretome product that contains many different classes of biomolecules capable of modifying cell function such as chemokines, cytokines, growth factors and RNA species capable of immunomodulatory and regenerative activity. The EVs may act through multiple mechanisms of action to direct the regenerative and anti-inflammatory processes of the BM-MSC from which they are derived.[33, 34]\u0026nbsp;While this study was not designed to prove efficacy or mechanism, the reduction of all four measured markers of systemic inflammation is consistent with a potential immunomodulatory effect of the IP (Online Resource Figure 3) and further study of this potential mechanism will be pursued. This secretome based therapeutic approach bypasses the challenges of direct allogeneic or autologous viable BM-MSC transplantation.[17, 35]\u0026nbsp;EVs easily pass through capillaries, making them a safer option for intravenous administration in contrast to cellular therapies. The IP is not subject to cell therapy associated issues of viability and unregulatable shifts in potency and efficacy profiles once delivered into the patient.\u0026nbsp;As shown here and in previous studies, the IP is extremely safe when administered intravenously. In addition, the trial herein is the first to show an EV product with potential survival benefit that, in phase 3, may prove superior to the clinical trial results from the aforementioned therapeutic candidates.\u003c/p\u003e\n\u003cp\u003eWhile this represents the largest expanded access program using an EV product for COVID-19, there are limitations to this study. First, there is no comparison group with placebo or variable dosing to understand the true efficacy benefit. Nor does the study address the optimal dose or dosing interval or the safety of such optimal protocols. Second, the protocol enrolled a broad range of respiratory failure including patients on noninvasive respiratory support to those on invasive respiratory support with mechanical ventilation. Third, while all included patients met criteria for moderate to severe ARDS, the protocol was not written to compare efficacy between patient phenotype, or ARDS phenotype. Last, it is unclear at this time why the IP appears to have a greater impact in a younger patient cohort.\u003c/p\u003e\n\u003cp\u003eGiven the preliminary results demonstrated by the IP, the FDA issued a regenerative medicine advanced therapeutic (RMAT) designation to facilitate a faster time to approval of the IP for treatment of severe or critical confirmed COVID-19. A BM-MSC EV enriched secretome product that is manufactured to consistent quality standards represents a novel, safe therapeutic candidate with potential for the treatment of COVID-19 induced and all-cause ARDS, and this potential is currently being fully evaluated with the IP in a Phase 3 clinical trial (NCT05354141).\u003c/p\u003e"},{"header":"EXPERIMENTAL PROCEDURES","content":"\u003cp\u003e\u003cstrong\u003e\u003cu\u003eDesign\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA prospective, multi-center, expanded access trial was conducted. \u0026nbsp;Enrollment for DB-EF-EXPANDEDACCESS-001 began in December 2020 and reached midpoint in December of 2022. \u0026nbsp;Five clinical trial sites in the United States actively participated in patient recruitment and enrollment under IND 21669. Patients with severe or critical COVID-19 who met modified Berlin criteria for acute respiratory distress syndrome (ARDS) as defined by onset of symptoms within one week of insult, respiratory failure not fully explained by cardiac failure or fluid overload, PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e \u0026pound; 200, PEEP \u0026gt;5 cm H2O, and bilateral opacities not fully explained by effusions or lung collapse were offered enrollment (Table 1).[36]\u003c/p\u003e\n\u003cp\u003eSee Figure 1 for CONSORT diagram for patient screening and enrollment. \u0026nbsp;We support inclusive, diverse, and equitable conduct of research.\u003c/p\u003e\n\u003cp\u003eEach lot of the IP meets stringent release specifications, including proteomic, mRNA and miRNA characterization as previously described in greater detail.[37] \u0026nbsp;Briefly, the IP is manufactured per FDA guidance for Current Good Manufacturing Practices (cGMP) with all manufacturing processes controlled under a Quality Management System, and implementation of lot-specific master batch records and specified release criteria for each lot of IP. The size and quantity of EVs and the presence of a specific surface marker expression profile are confirmed. \u0026nbsp;Identity assays are combined with validated potency assays to demonstrate the mechanism of action is functional. A 15 mL dose provides 1.2 x 10\u003csup\u003e12\u003c/sup\u003e EV particles.\u003c/p\u003e\n\u003cp\u003ePatients (n=103) were enrolled in the open label prospective DB-EF-EXPANDEDACCESS-001. After informed consent, patients received a 100 mL intravenous infusion over 60 minutes: 15 mL IP with 85 mL NS. \u0026nbsp;A repeat of the same study treatment occurred on Day 4 and Day 7 if the patient had not recovered (SpO\u003csub\u003e2\u003c/sub\u003e \u0026ge;93% on room air or PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u0026nbsp;\u003c/sub\u003e\u0026ge;300 mmHg). All patients were followed for 60 days, or until hospital discharge or death. \u0026nbsp;The trial protocol was approved by the institutional review board (IRB) at each site (or a centralized IRB as applicable) and overseen by an independent data and safety monitoring board (DSMB). Written informed consent (or consent by other IRB-approved process) was obtained from each patient or patient\u0026rsquo;s legally authorized representative if the patient was unable to provide consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eObjectives and Outcomes\u003c/u\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint was all-cause 60-day binomial mortality. Secondary endpoints included 1) treatment-emergent SAEs defined as any SAEs starting on or after the first dose date up to 30 days after the last dose, 2) ventilation-free days (VFDs) within the first 60-day follow-up, and 3) time to hospital discharge. Exploratory outcome measurements for acute phase reactants including CRP, D-dimer and ferritin and immune cell subset counts measured up to Day 61, Sequential Organ Failure Assessment (SOFA) scores measured as change from baseline to Day 15, and\u0026nbsp;PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e change from baseline to Day 7.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eMeasures\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were assessed daily from Day 1 to Day 60 during hospitalization. All treatment emergent adverse events (TEAEs), serious adverse events (SAEs) and grade 3 or 4 adverse events (AEs) representing increased severity from Day 1, and any grade suspected drug-related hypersensitivity reactions were recorded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eStatistical Analysis\u0026nbsp;\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data underlying this article are available in this article. This study used all treated participants who received at least a partial dose of the IP treatment regimen for efficacy and safety endpoints. Pre-defined sub-group analysis of 60-day all-cause mortality was performed on age groups, to investigate whether treatment with IP had more of an effect on outcome in specific patient groups.[21] \u0026nbsp; Missing data was not imputed, and the results were summarized based on available data.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eARDS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAcute respiratory distress syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBM-MSC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBone marrow mesenchymal stem cell\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eExtracellular vesicle\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInterquartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePEEP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePositive end expiratory pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSerious adverse event\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSOFA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSequential organ failure assessment\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTEAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTreatment emergent adverse event\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u0026nbsp; Sponsors (Direct Biologics, LLC) funded the study, provided ExoFlo, interpreted the data and drafted the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u003c/strong\u003e\u0026nbsp; Timothy A. Moseley: CSO at Direct Biologics, John T. Ransom: Sr. Medical Writer at Direct Biologics, Sascha Qian: prior Associate CMO at Direct Biologics, Vikram Sengupta: prior CMO at Direct Biologics\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval:\u0026nbsp;\u003c/strong\u003e The trial protocol was approved by the institutional review board (IRB) at each site (or a centralized IRB as applicable) and overseen by a data and safety monitoring board (DSMB) that was fully independent of both study sponsor and director.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate:\u003c/strong\u003e\u0026nbsp; Written informed consent (or consent by other IRB-approved process) was obtained from each patient, or patient\u0026rsquo;s legally authorized representative if the patient was unable to provide consent, following a discussion of informed consent principles with the investigator.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication:\u0026nbsp;\u003c/strong\u003eConsent for publication is contained within the informed consent form and permission is granted upon signing the consent form.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Material:\u003c/strong\u003e\u0026nbsp; \u0026nbsp;Additional data may be made available upon reasonable request to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode Availability\u003c/strong\u003e: \u0026nbsp;Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e VS: protocol design, interpretation of data, editing manuscript; SQ: protocol design, interpretation of data, editing manuscript; JTR: protocol design, interpretation of data, editing manuscript; SS: protocol design, interpretation of data, editing manuscript; DJP: enrollment of patients, protocol design, editing manuscript; TIM: enrollment of patients, protocol design, editing manuscript; BPW: enrollment of patients, protocol design, editing manuscript; JJW: enrollment of patients, protocol design, editing manuscript; MA: enrollment of patients, protocol design, editing manuscript; JMM: enrollment of patients, protocol design, editing manuscript; TAM: protocol design, drafting and finalizing manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLi, X., \u0026amp; Ma, X. 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Remdesivir: Quo vadis? \u003cem\u003eBiochemical pharmacology\u003c/em\u003e, \u003cem\u003e193\u003c/em\u003e, 114800.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrundeis, F., Ansems, K., Dahms, K., et al. (2023). Remdesivir for the treatment of COVID-19. \u003cem\u003eThe Cochrane database of systematic reviews\u003c/em\u003e, \u003cem\u003e1\u003c/em\u003e(1), Cd014962.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHsu, J. Y., Mao, Y. C., Liu, P. Y., \u0026amp; Lai, K. L. (2021). Pharmacology and Adverse Events of Emergency-Use Authorized Medication in Moderate to Severe COVID-19. \u003cem\u003ePharmaceuticals (Basel Switzerland)\u003c/em\u003e 14(10).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTiseo, G., Barbieri, C., Galfo, V., et al. (2023). 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Concise review: Mesenchymal stem cells for acute lung injury: role of paracrine soluble factors. \u003cem\u003eStem Cells\u003c/em\u003e, \u003cem\u003e29\u003c/em\u003e(6), 913\u0026ndash;919.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYu, B., Zhang, X., \u0026amp; Li, X. (2014). Exosomes derived from mesenchymal stem cells. \u003cem\u003eInternational journal of molecular sciences\u003c/em\u003e, \u003cem\u003e15\u003c/em\u003e(3), 4142\u0026ndash;4157.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRiviello, E. D., Kiviri, W., Twagirumugabe, T., et al. (2016). Hospital Incidence and Outcomes of the Acute Respiratory Distress Syndrome Using the Kigali Modification of the Berlin Definition. \u003cem\u003eAmerican journal of respiratory and critical care medicine\u003c/em\u003e, \u003cem\u003e193\u003c/em\u003e(1), 52\u0026ndash;59.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSengupta, V., Sengupta, S., Lazo, A. Jr., Hicok, K. C., Moseley, T., Response to, Lim (2020). re: Exosomes Derived from Bone Marrow Mesenchymal Stem Cells as Treatment for Severe COVID-19. \u003cem\u003eStem cells and development\u003c/em\u003e 29(14), 879\u0026ndash;881.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Inclusion and Exclusion Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"630\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInclusion Criteria:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 492px;\"\u003e\n \u003col start=\"1\" type=\"1\"\u003e\n \u003cli\u003eProvision of informed consent by self or proxy.\u003c/li\u003e\n \u003cli\u003eStated willingness to comply with study protocol. \u0026nbsp;\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eMale or female of any age \u0026ge; 18 years of age\u003c/li\u003e\n \u003cli\u003eMay be pregnant unless the patient has one or more conditions listed under Exclusion Criteria #4. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePositive Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) SARS-CoV-2. \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eModerate to severe ARDS as defined by timing within 1 week of known clinical insult or new or worsening respiratory symptoms, bilateral opacities not fully explained by effusions or lung collapse, and respiratory failure not fully explained by cardiac failure or fluid overload, and PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e \u0026pound; 200 mmHg. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAcute presentation of hypoxic respiratory failure requiring noninvasive oxygen support OR mechanical ventilation (MV).\u003c/li\u003e\n \u003cli\u003eAgreement to use highly effective birth control contraception if of reproductive age and potential. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\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: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eExclusion Criteria:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 492px;\"\u003e\n \u003col start=\"1\" type=\"1\"\u003e\n \u003cli\u003eActive malignancy requiring treatment within the last five years.\u003c/li\u003e\n \u003cli\u003eEligibility for enrollment in Protocol DB-EF-PhaseII-001. \u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePatients who are not full code. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePregnant patients with current or past history of eclampsia, preeclampsia, hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome during pregnancy. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eNew York Heart Association (NYHA) Functional Class III (symptoms present during ordinary activities) or IV Heart Failure (symptoms present at rest) or listed for heart transplant. \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eChronic Kidney Disease (CKD) Stage IV (GFR 15-29 mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e) and Stage V (GFR \u0026lt; 15 mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e) or listed for kidney transplant. \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eHepatic Impairment with Model for End-Stage Liver Disease (MELD) score \u0026ge; 30 or listed for liver transplant.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePatients on Extracorporeal Membrane Oxygenation. \u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Demographics and Baseline Characteristics (Safety Analysis Set).\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 343px;\"\u003e\n \u003cp\u003eDemographics and Baseline Characteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112px;\"\u003e\n \u003cp\u003eStatistics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003e(IP 15 mL up to 3 Doses)\u003cbr\u003e\u0026nbsp;(N=103)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 343px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e56.7 (16.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e22, 90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 343px;\"\u003e\n \u003cp\u003eAge \u0026ge; 65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e36 (35.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eAge \u0026lt; 65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e67 (65.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 343px;\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\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: 343px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e58 (56.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e45 (43.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 343px;\"\u003e\n \u003cp\u003eRace\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\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: 343px;\"\u003e\n \u003cp\u003eAmerican Indian or Alaska Native\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eAsian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e8 (7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eBlack or African American\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e13 (12.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eNative Hawaiian or Other Pacific Islander\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e77 (74.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eUnknown or Other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e5 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 343px;\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003csup\u003ea\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e102\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e34.147 (8.9523)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e18.16, 66.76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 343px;\"\u003e\n \u003cp\u003eRespiratory Rate (breaths/min)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e25.0 (7.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e11, 46\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 343px;\"\u003e\n \u003cp\u003eTime from the First Covid-19 Diagnosis to First IP Dose Date (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e8.5 (7.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1, 50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 343px;\"\u003e\n \u003cp\u003eTime from Screening Visit to First IP Dose Date (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1.5 (0.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1, 4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 343px;\"\u003e\n \u003cp\u003eTotal SOFA Score\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e3.2 (1.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e2, 12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 343px;\"\u003e\n \u003cp\u003eP/F Ratio (mmHg)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e118.454 (50.9406)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e45, 245\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 343px;\"\u003e\n \u003cp\u003ePrior Therapy\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eRemdesivir\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e57 (55.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003ePlasma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eDexamethasone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e98 (95.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 343px;\"\u003e\n \u003cp\u003eMechanical Ventilation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\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: 343px;\"\u003e\n \u003cp\u003eIntubated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e11 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eNon-Intubated\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e92 (89.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eIntubated (MV) on Study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003eTime on Intubation (MV) (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e9.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e(1\u003csup\u003est\u003c/sup\u003e, 3\u003csup\u003erd\u003c/sup\u003e Quartiles)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e(3.0, 17.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 343px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1, 37\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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\u003csup\u003ea\u003c/sup\u003eBaseline is the last measure prior to the first dose of IP (Day 0 or Day 1 5 min before dosing).\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003eIf the agent started prior to the first dose of IP regardless of its end date.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec\u003c/sup\u003eAll patients that were not intubated were on non-invasive ventilation of BiPAP or CPAP with a minimum of 5L 02/min\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Overall Summary of Safety (Safety Analysis Set)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 460px;\"\u003e\n \u003cp\u003eSafety Parameter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 164px;\"\u003e\n \u003cp\u003e(IP 15 mL up to 3 Doses)\u003cbr\u003e\u0026nbsp;(N=103)\u003cbr\u003e\u0026nbsp;n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 624px;\"\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: 460px;\"\u003e\n \u003cp\u003eAny TEAEs\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\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: 460px;\"\u003e\n \u003cp\u003eAny Grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e76 (73.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 460px;\"\u003e\n \u003cp\u003eGrade 3 or 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e14 (13.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 624px;\"\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: 460px;\"\u003e\n \u003cp\u003eSerious TEAEs\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\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: 460px;\"\u003e\n \u003cp\u003eAny Grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e41 (39.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 460px;\"\u003e\n \u003cp\u003eGrade 3 or 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e13 (12.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 624px;\"\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: 460px;\"\u003e\n \u003cp\u003eIP-Related TEAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e1 (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 624px;\"\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: 460px;\"\u003e\n \u003cp\u003eIP-Related Serious TEAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 624px;\"\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: 460px;\"\u003e\n \u003cp\u003eTEAEs That Led to Dose Interruption\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e2 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 624px;\"\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: 460px;\"\u003e\n \u003cp\u003eTEAEs That Led to Missing Dose or Discontinued the Treatment Early\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e1 (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 624px;\"\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: 460px;\"\u003e\n \u003cp\u003eTEAEs That Led to Death\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e28 (27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 624px;\"\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: 460px;\"\u003e\n \u003cp\u003eIP Infusion Reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 624px;\"\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\u003eTEAE = Treatment-Emergent Adverse Events, are defined as any adverse event that started between the first dose date and 30 days post the last dose date, inclusively.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eToxicity grades of adverse events are evaluated based on criteria of NCI-CTCAE v5.0. Each subject is counted once to the worst grade at subject-level.\u003c/p\u003e\n\u003cp\u003eNote: Related = Definitely, Probably, or Potentially Related.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. Summary of Efficacy (Full Analysis Set).\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 302px;\"\u003e\n \u003cp\u003eStudy Endpoints\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003eStatistics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 164px;\"\u003e\n \u003cp\u003e(IP 15 mL up to 3 Doses)\u003cbr\u003e\u0026nbsp;(N=103)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 302px;\"\u003e\n \u003cp\u003eSubjects Who Discharged from Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e68 (66.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 302px;\"\u003e\n \u003cp\u003eTime to Discharge (KM)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e11.0 days\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e(1st, 3rd Quartiles)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e(5.0, NR)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 302px;\"\u003e\n \u003cp\u003eMean Time to Discharge (Restricted to Discharged Subjects)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e9.9 days (10.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e1, 47\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 302px;\"\u003e\n \u003cp\u003eSubjects Who Died Within 30 Days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e27 (26.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eSubjects Who Died Within 60 Days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e30 (29.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e95% CI (exact)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e20.6, 38.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 302px;\"\u003e\n \u003cp\u003eMedian Time to Death (KM)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 302px;\"\u003e\n \u003cp\u003eMortality Rate at 15 Days (KM)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e% (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e19.1 (12.6, 28.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eMortality Rate at 30 Days (KM)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e% (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e27.3 (19.6, 37.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eMortality Rate at 60 Days (KM)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e% (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e30.6 (22.5, 40.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 302px;\"\u003e\n \u003cp\u003eMean Time to Death (Restricted to Subjects Who Died)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e16.2 days (12.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e6, 50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 302px;\"\u003e\n \u003cp\u003e\u003csup\u003ea\u003c/sup\u003ePaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e Ratio Increase from Baseline to Day 7 (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e115.149 (125.2062)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e0, 617.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 302px;\"\u003e\n \u003cp\u003e\u003csup\u003eb\u003c/sup\u003eVentilation-Free Days (within 60 Days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e40.8 (25.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e0, 61\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 302px;\"\u003e\n \u003cp\u003eDay 15 SOFA Score Change from Baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e1.2 (4.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e-6, 9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\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: 302px;\"\u003e\n \u003cp\u003eDay 29 SOFA Score Change from Baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e-0.6 (3.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e-6, 7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\u003e\n \u003cp\u003eKM = Kaplan Meier method, NR = Not Reached.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ea\u003c/sup\u003ePaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e ratio: All treated subjects with baseline and at least one PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e ratio measured at Day 4 or 7. For missing Day 7 data, 380 mmHg was assigned for discharged patients, and no change (0) was assigned to patients with negative change from the baseline or died before Day 7.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003eb\u003c/sup\u003eVentilation-free days: days when patients are not on mechanical ventilation within 60 days of follow-up.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5. Summary of Efficacy by Age Group (Full Analysis Set)\u003c/strong\u003e\u003c/p\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 240px;\"\u003e\n \u003cp\u003eStudy Endpoints\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 125px;\"\u003e\n \u003cp\u003eStatistics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 130px;\"\u003e\n \u003cp\u003eAge \u0026ge; 65\u003cbr\u003e\u0026nbsp;(N=36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 130px;\"\u003e\n \u003cp\u003eAge \u0026lt; 65\u003cbr\u003e\u0026nbsp;(N=67)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\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: 240px;\"\u003e\n \u003cp\u003eSubjects Who Discharged from Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e20 (55.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e48 (71.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\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: 240px;\"\u003e\n \u003cp\u003eTime to Discharge (KM)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e19.0 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e9.0 days\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e(1st, 3rd Quartiles)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e(5.5, NR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e(5.0, NR)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\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: 240px;\"\u003e\n \u003cp\u003eMean Time to Discharge (Restricted to Discharged Subjects)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e10.0 days (10.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e9.8 days (10.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e3, 47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e1, 44\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\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: 240px;\"\u003e\n \u003cp\u003eSubjects Who Died Within 30 Days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e15 (41.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e12 (17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003eSubjects Who Died Within 60 Days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e15 (41.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e15 (22.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e95% CI (exact)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e25.5, 59.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e13.1, 34.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\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: 240px;\"\u003e\n \u003cp\u003eMedian Time to Death (KM)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\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: 240px;\"\u003e\n \u003cp\u003eMortality Rate at 15 Days (KM)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e% (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e37.1 (23.5, 55.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e9.4 (4.3, 19.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003eMortality Rate at 30 Days (KM)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e% (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e43.1 (28.6, 61.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e18.8 (11.1, 30.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003eMortality Rate at 60 Days (KM)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e% (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e43.1 (28.6, 61.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e23.8 (15.1, 36.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\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: 240px;\"\u003e\n \u003cp\u003eMean Time to Death (Restricted to Subjects Who Died)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e10.5 days (5.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e21.9 days (14.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e6, 25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e7, 50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\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: 240px;\"\u003e\n \u003cp\u003e\u003csup\u003ea\u003c/sup\u003ePaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e Ratio Increase from Baseline to Day 7 (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e114.028 (124.0509)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e115.754 (126.8134)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e0, 396.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e0, 617.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\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: 240px;\"\u003e\n \u003cp\u003e\u003csup\u003eb\u003c/sup\u003eVentilation-Free Days (within 60 Days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e33.4 (26.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e44.7 (24.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e0, 61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e0, 61\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\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: 240px;\"\u003e\n \u003cp\u003eDay 15 SOFA Score Change from Baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e-2.0 (2.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e2.2 (4.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e-6, 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e-6, 9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\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: 240px;\"\u003e\n \u003cp\u003eDay 29 SOFA Score Change from Baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e-3.5 (2.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e0.4 (3.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 240px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e-6, 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e-3, 7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\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\u003eKM = Kaplan Meier method, NR = Not Reached.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003ePaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e ratio: All treated subjects with baseline and at least one PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e ratio measured at Day 4 or 7. For missing Day 7 data, 380 mmHg was assigned for discharged patients, and no change (0) was assigned to patients with negative change from the baseline or died before Day 7.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003eVentilation-free days: days when patients are not on mechanical ventilation within 60 days of follow-up.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"stem-cell-reviews-and-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"stcr","sideBox":"Learn more about [Stem Cell Reviews and Reports](https://www.springer.com/journal/12015)","snPcode":"12015","submissionUrl":"https://submission.nature.com/new-submission/12015/3","title":"Stem Cell Reviews and Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Extracellular vesicle, bone marrow mesenchymal stem cell, COVID-19, safety, efficacy","lastPublishedDoi":"10.21203/rs.3.rs-8890163/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8890163/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe safety of an extracellular vesicle (EV) enriched secretome from bone marrow mesenchymal stem cells (BM-MSCs) was evaluated in a multi-site, prospective, expanded access trial as potential treatment for respiratory failure due to COVID-19. Subjects (103) received up to three doses of 15 mL IP every 72 hours. The primary outcome was all cause 60-day mortality. Secondary outcomes included serious adverse events. One TEAE (grade 1 hyperpigmentation at the infusion site) related to IP occurred. 60-day mortality was 29% for all patients, 22.4% in patients \u0026lt;65 years and 41.7% in patients ≥65 years. \u0026nbsp;Mean ventilation free days was 40.8 for all patients, 44.7 days in patients \u0026lt;65 years and 33.4 days in patients ≥65 years. Median time to hospital (IQR) discharge by Kaplan-Meier was 11 (5.0-NR) days in all patients, 9 (5.0-NR) days in patients \u0026lt;65 years and 19 (5.5-NR) days in patients ≥65 years. The IP (15 mL dose) is safe in patients with severe or critical COVID-19 respiratory failure.\u003c/p\u003e","manuscriptTitle":"Bone Marrow Mesenchymal Stem Cell Extracellular Vesicle Treatment of Respiratory Failure from COVID-19: Endpoint Analysis of Expanded Access Safety Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-22 17:08:39","doi":"10.21203/rs.3.rs-8890163/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-28T06:55:01+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-26T09:33:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-20T15:16:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"52314692642914037213910083401817580766","date":"2026-02-19T08:41:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"320348350379074036817462147689101325672","date":"2026-02-19T07:32:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"29021038489417839294838213422232344900","date":"2026-02-19T07:13:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"336647316882176402164613351120323654630","date":"2026-02-18T16:36:05+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-18T15:45:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-18T02:20:12+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-18T02:20:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"Stem Cell Reviews and Reports","date":"2026-02-16T06:08:06+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"stem-cell-reviews-and-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"stcr","sideBox":"Learn more about [Stem Cell Reviews and Reports](https://www.springer.com/journal/12015)","snPcode":"12015","submissionUrl":"https://submission.nature.com/new-submission/12015/3","title":"Stem Cell Reviews and Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"ac415d49-dd3f-4609-83a6-30c08d3e4623","owner":[],"postedDate":"February 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-20T11:38:59+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-22 17:08:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8890163","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8890163","identity":"rs-8890163","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}