Intravenous Aviptadil for Critical COVID-19 With Respiratory Failure (COVID-AIV)
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|ClinicalTrials.gov Identifier: NCT04311697|
Recruitment Status : Active, not recruiting
First Posted : March 17, 2020
Last Update Posted : December 29, 2020
|Condition or disease||Intervention/treatment||Phase|
|Critical COVID-19 With Respiratory Failure Acute Respiratory Distress Syndrome (ARDS) Corona Virus Infection Acute Lung Injury||Drug: Aviptadil by intravenous infusion + standard of care Drug: Normal Saline Infusion + standard of care||Phase 2 Phase 3|
Expanded Access : An investigational treatment associated with this study is available outside the clinical trial. More info ...
Acute Lung Injury, which triggers Critical COVID-19 is a known lethal complication of Corona Virus (SARS-CoV-2) infection. Conventional medical therapy, including intensive care and respiratory support is associated with an 80% mortality. Aviptadil, a synthetic form of Human Vasoactive Intestinal Polypeptide (VIP) has been awarded FDA Orphan Drug Designation for the treatment of ARDS and admitted to the FDA CoronaVirus Technology Accelerator Program.
VIP binds to VPAC1 receptors on the pulmonary Alveolar Type II (ATII) cell. ATII cells comprise only 5% of lung epithelial cells but are critical for oxygen transfer, surfactant production, and maintenance of Alveolar Type 1 cells. 70% of VIP binds to this receptor. The Type II cell is also the cell selectively attacked by the SARS-CoV-2 virus via the ACE2 surface receptor.
Nonclinical studies demonstrate that VIP is highly concentrated in the lung and specifically bound to the ATII cell, where it prevents NMDA-induced caspase-3 activation in the lung, inhibits IL6 and TNFa production, protects against HCl-induced pulmonary edema, and upregulates surfactant production, These and other effects have been observed in numerous animal model systems of lung injury in mice, rats, guinea pigs, sheep, swine, and dogs. In these models, Aviptadil restores barrier function at the endothelial/alveolar interface and thereby protects the lung and other organs from failure.
Aviptadil ihas a demonstrated 20 year history of safety in phase 2 trials for Sarcoid, Pulmonary Fibrosis, Bronchospasm, and a phase I trial in ARDS. In that phase I trial, 8 patients with severe ARDS on mechanical ventilation were treated with ascending doses of VIP. Seven of the 8 patients were successfully extubated and were alive at the five day timepoint. Six left the hospital and one died of an unrelated cardiac event.
Five phase 2 trials of aviptadil have been conducted under European regulatory authority. Numerous healthy volunteer studies have shown that i.v. infusion of Aviptadil is well tolerated with few adverse effects including alterations in blood pressure, heart rate, or ECG. In addition to published studies of human use, Aviptadil has been used on a compounded basis in certain ICUs for many years in the belief that it preserves life and restores function in pulmonary hypertension, ARDS, and Acute Lung Injury (ALI).
In this study, patients who are hospitalized for Critical COVID-19 infection with respiratory failure will be randomly allocated to Aviptadil administered by intravenous infusion in addition to maximal intensive care vs. maximal intensive care alone. Primary endpoints will be improvement in blood oxygenation and mortality.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||196 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||Multicenter trial, initially conducted at a single center with a safety/futility assessment following enrollment of 30 patients, expanded to 196 total patients at 12 study sites|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Masking Description:||Randomized, placebo-controlled trial with identical drug and placebo infusion bags|
|Official Title:||ZYESAMI (Aviptadil) for the Treatment of Critical COVID-19 With Respiratory Failure|
|Actual Study Start Date :||May 15, 2020|
|Estimated Primary Completion Date :||January 21, 2021|
|Estimated Study Completion Date :||February 28, 2021|
Experimental: Aviptadil IV in escalating doses + standard of care
Patients will be administered Aviptadil IV in escalating doses of 50 pmol, 100 pmol, 150 pmol/kg/hr
Drug: Aviptadil by intravenous infusion + standard of care
Aviptadil by intravenous infusion + standard of care (SOC). SOC is defined not to include extracorporeal mechanical oxygenation. Those requiring ECMO will be withdrawn from the study as treatment failures.
Other Name: ZYESAMI (aviptadil) +SOC
Experimental: Placebo + standard of care
Patients will first be treated with placebo infusion + maximal intensive care
Drug: Normal Saline Infusion + standard of care
Saline by intravenous infusion + standard of care (SOC). SOC is defined not to include extracorporeal mechanical oxygenation. Those requiring ECMO will be withdrawn from the study as treatment failures.
Other Name: Placebo+SOC
- Resolution of Respiratory Failure [ Time Frame: Day 0 through day 28 ]Cumulative distribution of the time to respiratory failure resolution with concurrent survival through day 28
- Improvement on NIAID Scale (key secondary measure) [ Time Frame: Day 0 through day 28 ]Achievement of score 6-8 on NIAID Ordinal Scale through day 28
- Survival through day 28 and day 60 [ Time Frame: Day 0 through day 28 ]Survival probability on Kaplan Meier lifetable through day 28 and day 60
- Time to ICU discharge [ Time Frame: Day 0 through day 28 ]Time to discharge from Intensive Care Unit
- Time on ventilation [ Time Frame: Day 0 through day 28 ]Time on mechanical ventilation, non-invasive ventilation, or high-flow nasal oxygen
- Time to extubation [ Time Frame: Day 0 through day 28 ]Time to extubation (for those initially on mechanical ventilation)
- Time to discharge alive [ Time Frame: Day 0 through day 28 and day 60 ]Time to discharge alive
- Multi-organ failure free days [ Time Frame: Day 0 through day 28 ]Days free of multisystem organ failure
- Respiratory Distress while on mechanical ventilation [ Time Frame: Day 0 through day 28 ]PaO2:FiO2 ratio
- Oxygenation index [ Time Frame: Day 0 through day 28 ]Oxygenation index
- Improvement in chest x-ray [ Time Frame: Day 0 through day 28 ]Improvement in chest x-ray by RALES score
- Improvement in inflammatory markers [ Time Frame: Day 0 through day 28 ]Improvement in IL-6, TNF alpha, and other inflammatory markers
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04311697
|United States, California|
|University of California - Irvine|
|Irvine, California, United States, 92697|
|United States, Florida|
|Miller School of Medicine / University of Miami Medical Center|
|Miami, Florida, United States, 33136|
|United States, Kentucky|
|University of Louisville|
|Louisville, Kentucky, United States, 40202|
|United States, New York|
|Robert I Grossman School of Medicine / NYU Langone Medical Center|
|New York, New York, United States, 10016|
|United States, Texas|
|Houston Methodist Hospital|
|Houston, Texas, United States, 77030|
|Study Chair:||Jonathan C Javitt, MD, MPH||NeuroRx, Inc.|