AV-001 for Hospitalized Patients With COVID-19 Disease
Study Details
Study Description
Brief 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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed 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
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: AV-001 Injection with standard of care (SOC). A total of 120 eligible patients (20 patients in each of cohort 1, 2 and 3 and 60 patients in cohort 4) 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). Doses of AV-001 Injection will start with 12.5 μg/kg/day in cohort 1 and are anticipated to increase to 25 μg/kg/day in cohort 2, 56 μg/kg/day in cohort 3 and to be determined (TBD) in cohort 4. The dose for cohort 4 will be determined by the Data Safety Monitoring Board (DSMB) based on emerging data from cohorts 1, 2 and 3. |
Drug: AV-001 Injection
AV-001 (mpaBr) Cl for Injection 2.5 mg/mL
|
| Placebo Comparator: AV-001 Placebo Injection with standard of care (SOC). A total of 120 eligible patients (20 patients in each of cohort 1, 2 and 3 and 60 patients in cohort 4) 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). |
Drug: AV-001 Placebo Injection
D-PBS
|
Outcome Measures
Primary Outcome Measures
- Safety and tolerability of multiple doses of IV administrations of AV-001 Injection compared with AV-001 placebo Injection in hospitalized patients with severe COVID-19 disease. [Up to Day 60]
Number of patients with any serious adverse event (SAE) (day 1 to 60/EOS) Number of patients with any treatment emergent adverse event (TEAE) (day 1 to 60/EOS) AE assessments
Secondary Outcome Measures
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by improvement on WHO COVID-19 CPS score and survival. [Up to Day 28]
Measured as proportion of patients achieving a 2-point improvement in WHO COVID-19 CPS score from baseline and alive by day 28.
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by time to first 2-point improvement on WHO COVID-19 CPS score. [Up to Day 28]
Measured as time to first 2-point improvement, displayed with a Kaplan-Meier lifetable.
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by survival at day 28. [Up to Day 28]
Measured as survival at day 28, displayed with a Kaplan- Meier lifetable.
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by progression to respiratory failure. [Up to Day 28]
Measured as proportion of patients that progress to respiratory failure by day 28.
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by progression to mechanical ventilation. [Up to Day 28]
Measured as proportion of patients that progress to mechanical ventilation by day 28.
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by 1-point improvement on WHO COVID-19 CPS score for 3 consecutive days. [Up to Day 28]
Measured as proportion of patients with disease improvement of at least 1 point on the WHO COVID-19 CPS for 3 consecutive days and sustained the improvement through day 28.
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by SpO2 saturation. [Up to Day 28]
Measured as proportion of patients achieving normalization (last oxygen saturation of arterial blood [SaO2] value > 95%).
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by oxygen delivery. [Up to Day 28]
Measured as the product of flow rate and volume per day.
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by acute kidney injury (KDIGO stage distribution over time). [Up to Day 28]
Measured as the acute kidney injury stage distribution over time using the Kidney Disease Improving Global Outcomes (KDIGO) definition of Acute Kidney Injury (AKI).
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by discharge from ICU and survival at day 28. [Up to Day 28]
Measured as proportion of patients alive and discharged from the intensive care unit (ICU) at day 28.
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by discharge from hospital and survival at day 28. [Up to Day 28]
Measured as proportion of patients alive and discharged from hospital at day 28.
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by time to hospital discharge status. [Up to Day 28]
Measured as time to hospital discharge status (discharge or day 28, whichever is earlier).
Other Outcome Measures
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by survival at day 60. [Up to Day 60]
Measured as alive at day 60, displayed with a Kaplan- Meier lifetable.
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by progression to respiratory failure. [Up to Day 14]
Measured as Proportion of patients that progress to respiratory failure by day 14.
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by progression to mechanical ventilation. [Up to Day 14]
Measured as proportion of patients that progress to mechanical ventilation by day 14.
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by improvement on WHO COVID-19 CPS score and survival. [Up to Day 14]
Proportion of patients achieving a 2-point improvement in WHO COVID-19 CPS score from baseline and alive by day 14.
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by discharge from ICU and survival at day 14. [Up to Day 14]
Measured as proportion of patients alive and discharged from the intensive care unit (ICU) at day 14.
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by discharge from hospital and survival at day 14. [Up to Day 14]
Measured as proportion of patients alive and discharged from hospital at day 14.
- Efficacy of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection in patients hospitalized with severe COVID-19 disease as measured by durable loss of eGFR (by day 28 and day 60) from baseline. [Up to Day 60]
Measured as durable loss of eGFR (by day 28 and day 60) from baseline (89-60 mL/min, 59-45 mL/min, 30-44 mL/min, <30 mL/min) or the development of severe AKI requiring continuous renal replacement therapy (CRRT), prolonged intermittent renal replacement therapy (PIRRT) or hemodialysis.
- Effect of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection on exploratory biomarker Tie2. [Up to Day 28]
Measured as ratio of phosphorylated Tie2/Total Tie2 using flow cytometry analysis.
- Effect of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection on exploratory biomarkers Angpt-1, Angpt-2, and circulating Tie2. [Up to Day 28]
Measured using quantitative ELISA.
- Effect of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection on disease biomarker IL-6 in patients with severe COVID-19 disease. [Up to Day 28]
Measured at screening and at pre-dose on days 2, 4, 7, 10, 13, 16, 19, 22, 25 and the earlier of day 28 or EOT using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay.
- Effect of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection on disease biomarker IL-8 in patients with severe COVID-19 disease. [Up to Day 28]
Measured at screening and at pre-dose on days 2, 4, 7, 10, 13, 16, 19, 22, 25 and the earlier of day 28 or EOT using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay.
- Effect of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection on disease biomarker sTNFr-1 in patients with severe COVID-19 disease. [Up to Day 28]
Measured at screening and at pre-dose on days 2, 4, 7, 10, 13, 16, 19, 22, 25 and the earlier of day 28 or EOT using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay.
- Effect of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection on disease biomarker MCP-1 in patients with severe COVID-19 disease. [Up to Day 28]
Measured at screening and at pre-dose on days 2, 4, 7, 10, 13, 16, 19, 22, 25 and the earlier of day 28 or EOT using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay.
- Effect of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection on disease biomarker IP-10 in patients with severe COVID-19 disease. [Up to Day 28]
Measured at screening and at pre-dose on days 2, 4, 7, 10, 13, 16, 19, 22, 25 and the earlier of day 28 or EOT using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay.
- Effect of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection on disease biomarker ICAM-1, in patients with severe COVID-19 disease. [Up to Day 28]
Measured at screening and at pre-dose on days 2, 4, 7, 10, 13, 16, 19, 22, 25 and the earlier of day 28 or EOT using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay.
- PK as measured by Cmax of AV-001 Injection in hospitalized patients with severe COVID-19 disease. [Up to Day 28]
Assessment of the PK of AV-001 Injection in hospitalized patients with severe COVID-19 disease using population PK for DL1, DL2 and DL3. PK measured as Cmax from sample timepoints Pre-dose, 5 min, 30 min, 1, 2, 4, and 24 hours post-dose on days 1, 7 and the earlier of day 28 or EOT.
- PK as measured by Tmax of AV-001 Injection in hospitalized patients with severe COVID-19 disease. [Up to Day 28]
Assessment of the PK of AV-001 Injection in hospitalized patients with severe COVID-19 disease using population PK for DL1, DL2 and DL3. PK measured as Tmax, from sample timepoints Pre-dose, 5 min, 30 min, 1, 2, 4, and 24 hours post-dose on days 1, 7 and the earlier of day 28 or EOT.
- PK as measured by AUC of AV-001 Injection in hospitalized patients with severe COVID-19 disease. [Up to Day 28]
Assessment of the PK of AV-001 Injection in hospitalized patients with severe COVID-19 disease using population PK for DL1, DL2 and DL3. PK measured as AUC from sample timepoints Pre-dose, 5 min, 30 min, 1, 2, 4, and 24 hours post-dose on days 1, 7 and the earlier of day 28 or EOT.
- Effect of multiple IV administrations of AV-001 Injection compared with AV-001 placebo Injection on SARS-CoV-2 viral load in patients with severe COVID-19 disease. [Up to Day 7]
SARS-CoV-2 variant identification and viral load measured using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) from a mid-nasal (or other respiratory) swab at screening and the earlier of day 7 or the EOT.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Able and willing to give signed informed consent
-
Hospitalized less than 48 hours with pneumonia and confirmed COVID-19 disease
-
Meet the criteria for severe COVID_19 disease at randomization defined as patients that have one or more of the following:
-
oxygen saturation as detected by pulse oximeter (SpO2) < 94% on room air at sea level
-
ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) < 300 mm Hg
-
respiratory rate > 30 breaths/min
-
lung infiltrates involving > 50% of lung parenchyma
-
Score of 5 or 6 on the WHO COVID-19 10-point Clinical Progression Scale (CPS) at randomization
-
Female patients of reproductive potential must be on an effective contraceptive method
Exclusion Criteria:
-
Pregnant and/or lactating women
-
Patients included in any other interventional trial
-
Body Mass Index (BMI) > 35
-
Use of endotracheal intubation and mechanical ventilation or extracorporeal membrane oxygenation (ECMO) at screening
-
Any concurrent serious medical condition or concomitant medication that would preclude participation in the study
-
Known history of human immunodeficiency virus and/or hepatitis (acute or chronic)
-
Severe renal insufficiency or end-stage renal disease
-
Recent (within past 2 months) major surgery or central venous access device placement
-
Any thromboembolic event within the past 3 months
-
Symptomatic congestive heart failure or symptomatic or poorly controlled cardiac arrhythmia > class II as per New York Heart Association (NYHA) classification
-
History of autonomic disorders or uncontrolled hypotension
-
Hypersensitivity to drug products containing polyethylene glycol (PEG)
-
Any other condition which the Principal Investigator feels may jeopardize the safety of the patient or the objectives of the study
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University Medical Center of Southern Nevada | Las Vegas | Nevada | United States | 89102 |
Sponsors and Collaborators
- Vasomune Therapeutics, Inc.
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- AV001-004
- CDMRP-PR203503