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Clinical Trial Summary

A Phase 2a, randomized, double-blind, placebo-controlled, dose-escalation study in patients hospitalized with confirmed severe coronavirus disease 2019 (COVID-19). The purpose of this study is to examine the safety, tolerability and efficacy of AV-001 Injection administration daily to the earlier of day 28 or EOT (day prior to hospital discharge) to patients with severe COVID-19 disease. A total of 120 eligible patients (20 patients in each of cohort 1, 2 and 3 and 60 patients in cohort 4) will be recruited from up to 20 participating institutions/hospitals. Patients will be randomized in a 1:1 ratio to receive either AV-001 Injection or AV-001 placebo Injection, together with standard of care (SOC).


Clinical Trial Description

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a coronavirus novel to the human population, discovered in December 2019 and is currently the cause of a global pandemic. Since the emergence of coronavirus Disease 2019 (COVID-19) in Wuhan, China on 29 December 2019, it has spread rapidly across the globe, with over 212 million cases and more than 4,438,657 deaths reported worldwide as of 23 August 2021. Large observational studies suggest patients with COVID-19-associated ARDS have similar respiratory system mechanics to patients with ARDS from other causes. SOC for patients with ARDS remains limited with current interventions that focus primarily on supportive therapy, including fluid management strategies and further injury prevention via lung protective ventilation. Emerging evidence suggests pulmonary endothelial cells contribute to the initiation and propagation of ARDS in COVID-19 by altering vessel barrier integrity, promoting a coagulative state, inducing vascular inflammation (endotheliitis) and mediating inflammatory cell migration. In ARDS patients, the host vascular response (HVR) becomes unrestrained, resulting in vascular barrier dysfunction, pulmonary edema and, ultimately, life-threatening impairment of lung function. Central to the pathogenesis of ARDS is the accumulation of pulmonary fluid within the interstitium and alveolus owing to increased permeability of the lung microvasculature and loss of endothelial barrier integrity. Deterioration of vascular barrier function results in compromised gas exchange, impaired lung function and in severe cases, death. Large observational studies suggest patients with COVID-19-associated ARDS have similar respiratory system mechanics to patients with ARDS from other causes. SOC for patients with ARDS remains limited with current interventions that focus primarily on supportive therapy, including fluid management strategies and further injury prevention via lung protective ventilation. AV-001 is a synthetic Angiopoietin-1 (Angpt-1) mimetic that has been shown to activate the Tie2 receptor tyrosine kinase; a transmembrane protein target most highly expressed on the surface of endothelial cells in the vasculature. The Tie2/Angiopoietin signaling axis has been identified as a nonredundant gatekeeper of vascular homeostasis. In healthy individuals, Tie2 is highly activated and signals the endothelium to fortify intracellular junctions and reduce expression of adhesion molecules, which serve as leukocyte tethers upon inflammation. As such, homeostatic activation results in the promotion of barrier defense against vascular leakage. A total of 120 eligible patients (20 patients each in cohorts 1, 2 and 3 and 60 patients in cohort 4) will be recruited from participating institutions / hospitals. Patients will be randomized in a 1:1 ratio to receive either AV-001 Injection or AV-001 placebo Injection, together with SOC. All patients will receive supportive care according to the SOC for the trial site hospital likely to include remdesivir and or dexamethasone. Study drug will be administered by bolus IV injection (< 60 seconds). Doses of AV-001 Injection to be administered will start with the lowest proposed dose of 12.5 μg/kg/day in cohort 1 (DL1) and are anticipated to increase to 25 μg/kg/day in cohort 2 (DL2), 56 μg/kg/day in cohort 3 (DL3) and to be determined (TBD) based on recommendation from the DSMB for cohort 4 (DL4). The dose for cohort 4 will be chosen based on available safety and efficacy data obtained from all patients completing DL1, DL2 and DL3. DL4 may be an intermediate dose level, repeat of an earlier dose level (DL1, DL2, or DL3) or expansion of earlier dose level cohort (DL1, DL2, or DL3). Based on emerging data, a decision to enroll a fifth cohort (n=20 to increase the sample size to n=140) may also be made for the purpose of investigating an intermediate dose level, evaluating effects in patients with a different baseline Clinical Progression Scale (CPS) score or to provide comparative data regarding AV-001 Injection in patients with other respiratory viruses. The study population for the Phase 2a study will consist of patients with severe COVID-19 disease which is defined by oxygen saturation (SpO2) < 94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) < 300 mm Hg, respiratory frequency > 30 breaths/min or lung infiltrates > 50% as per the NIH COVID-19 Treatment Guidelines. Patients with PaO2/FiO2 < 300 mm Hg but not requiring mechanical ventilations are eligible for this study. Patients hospitalized with a baseline WHO COVID-19 Clinical CPS score of 5 and 6, on the 10-point scale will be eligible for this study. ;


Study Design


Related Conditions & MeSH terms


NCT number NCT05123755
Study type Interventional
Source Vasomune Therapeutics, Inc.
Contact
Status Not yet recruiting
Phase Phase 2
Start date November 2021
Completion date June 2022

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