COVID-AIV: Intravenous Aviptadil for Critical COVID-19 With Respiratory Failure

Sponsor

NeuroRx, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT04311697

Collaborator

Lavin Consulting, LLC (Other)

196

Enrollment

Locations

Arms

9.3

Actual Duration (Months)

19.6

Patients Per Site

2.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Novel Corona Virus (SARS-CoV-2) is known to cause Respiratory Failure, which is the hallmark of Acute COVID-19, as defined by the new NIH/FDA classification. Approximately 50% of those who develop Critical COVID-19 die, despite intensive care and mechanical ventilation. Patients with Critical COVID-19 and respiratory failure, currently treated with high flow nasal oxygen, non-invasive ventilation or mechanical ventilation will be treated with ZYESAMI (aviptadil), a synthetic form of Human Vasoactive Intestinal Polypeptide (VIP) plus maximal intensive care vs. placebo + maximal intensive care. Patients will be randomized to intravenous Aviptadil will receive escalating doses from 50 -150 pmol/kg/hr over 12 hours.

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

Detailed Description

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 Design

Study Type:

Interventional

Actual Enrollment :

196 participants

Allocation:

Randomized

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 sitesMulticenter 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

Primary Purpose:

Treatment

Official Title:

ZYESAMI (Aviptadil) for the Treatment of Critical COVID-19 With Respiratory Failure

Actual Study Start Date :

May 15, 2020

Actual Primary Completion Date :

Feb 22, 2021

Actual Study Completion Date :

Feb 22, 2021

Arms and Interventions

Arm	Intervention/Treatment
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 Names: 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 Names: Placebo+SOC

Arm

Intervention/Treatment

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 Names:

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 Names:

Placebo+SOC

Outcome Measures

Primary Outcome Measures

Resolution of Respiratory Failure (Alive and Free of Respiratory Failure) [Day 0 through day 28 (interim) and 60]
Participant is Alive and Free of Respiratory Failure (without subsequent relapse over 7 days) determined as no longer requiring acute care or more than low flow oxygen

Secondary Outcome Measures

Survival through day 60 (key secondary) [Day 60]
Survival probability on logistic regression through day 60
Improvement on NIAID Scale (key secondary measure) [Day 0 through day 60]
Achievement of score 6-8 on NIAID Ordinal Scale through day 60
Time to ICU discharge [Day 0 through day 28 (interim) and 60]
Time to discharge from Intensive Care Unit
Time on ventilation [Day 0 through day 28 (interim) and 60]
Time on mechanical ventilation, non-invasive ventilation, or high-flow nasal oxygen
Time to extubation [Day 0 through day 28 (interim) and 60]
Time to extubation (for those initially on mechanical ventilation)
Time to discharge alive [Day 0 through day 28 (interim) and 60]
Time to discharge alive
Multi-organ failure free days [Day 0 through day 28 (interim) and 60]
Days free of multisystem organ failure

Other Outcome Measures

Respiratory Distress while on mechanical ventilation [Day 0 through day 28 (interim) and 60]
PaO2:FiO2 ratio
Oxygenation index as measured by PaO2:FiO2 [Day 0 through day 28 (interim) and 60]
Oxygenation index
Improvement in chest x-ray [Day 0 through day 28 (interim) and 60]
Improvement in chest x-ray by RALES score
Improvement in inflammatory markers [Day 0 through day 28 (interim) and 60]
Improvement in IL-6, TNF alpha, and other inflammatory markers

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 100 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Critical COVID-19 with respiratory failure
Physician determination that patient is on maximal conventional medical therapy

Exclusion Criteria:

Pregnancy (pregnant women may apply for open label treatment under compassionate care IND
Age <18 years
Mechanical ventilation for more than 7 days in primary cohort. Mechanical ventilation>21 days in the exploratory cohort
Mean Arterial Pressure < 65 mm Hg with use of pressor per ICU protocol
Irreversible condition (other than COVID-19) with projected fatal course
ECMO
Current or recent (within 30 d) enrollment in another investigational trial of anti-IL6 drug;
Active diagnosis of Acquired immune deficiency syndrome;
Transplant patients currently immunosuppressed;
Chemotherapy-induced neutropenia (granulocyte count <1000/mm3);
Cardiogenic shock; congestive heart failure - NYHA Class 3 or 4;
Recent myocardial infarction - within last 6 months and troponin > 0.5
Anuria (urine output < 50 ml/d) or other signs of multi-organ failure
Severe liver disease with portal hypertension;
Recent stroke or head trauma within last 12 months
Increased intracranial pressure, or other serious neurologic disorder;
Liquid Diarrhea more than 3x/day; defined as more than 3 non-bloody watery stools within a 24-hour period, requiring additional fluid and electrolyte supplementation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Jude Medical Center	Fullerton	California	United States	92835
2	University of California - Irvine	Irvine	California	United States	92697
3	Miller School of Medicine / University of Miami Medical Center	Miami	Florida	United States	33136
4	Baptist Hospital of Miami	Miami	Florida	United States	33176
5	University of Louisville Hospital	Louisville	Kentucky	United States	40202
6	Heartland/Mosaic Health	Saint Joseph	Missouri	United States	64506
7	Hendrick Health	Abilene	Texas	United States	79601
8	Texas Health Harris Methodist Hospital	Fort Worth	Texas	United States	76104
9	Texas Health Hospital Frisco	Frisco	Texas	United States	75033
10	Houston Methodist Hospital	Houston	Texas	United States	77030