Intravenous Aviptadil for Critical COVID-19 With Respiratory Failure (COVID-AIV)

• ClinicalTrials.gov Identifier: NCT04311697
• Recruitment Status: Completed
• First Posted: March 17, 2020
• Last Update Posted: September 13, 2021
• Sponsor: NeuroRx, Inc.
• Collaborator: Lavin Consulting, LLC
• Information provided by (Responsible Party): NeuroRx, Inc.

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

Expanded Access : An investigational treatment associated with this study is no longer available outside the clinical trial.   More info ...

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 (Clinical Trial)
• 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 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: February 22, 2021
• Actual Study Completion Date: February 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 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

Outcome Measures

Primary Outcome Measures :

1. Resolution of Respiratory Failure (Alive and Free of Respiratory Failure) [ Time Frame: 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 :

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

Other Outcome Measures:

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 100 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

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

Exclusion Criteria:

1. Pregnancy (pregnant women may apply for open label treatment under compassionate care IND
2. Age <18 years
3. Mechanical ventilation for more than 7 days in primary cohort. Mechanical ventilation>21 days in the exploratory cohort
4. Mean Arterial Pressure < 65 mm Hg with use of pressor per ICU protocol
5. Irreversible condition (other than COVID-19) with projected fatal course
6. ECMO
7. Current or recent (within 30 d) enrollment in another investigational trial of anti-IL6 drug;
8. Active diagnosis of Acquired immune deficiency syndrome;
9. Transplant patients currently immunosuppressed;
10. Chemotherapy-induced neutropenia (granulocyte count <1000/mm3);
11. Cardiogenic shock; congestive heart failure - NYHA Class 3 or 4;
12. Recent myocardial infarction - within last 6 months and troponin > 0.5
13. Anuria (urine output < 50 ml/d) or other signs of multi-organ failure
14. Severe liver disease with portal hypertension;
15. Recent stroke or head trauma within last 12 months
16. Increased intracranial pressure, or other serious neurologic disorder;
17. 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

United States, California

St. Jude Medical Center

Fullerton, California, United States, 92835

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

Baptist Hospital of Miami

Miami, Florida, United States, 33176

United States, Kentucky

University of Louisville Hospital

Louisville, Kentucky, United States, 40202

United States, Missouri

Heartland/Mosaic Health

Saint Joseph, Missouri, United States, 64506

United States, Texas

Hendrick Health

Abilene, Texas, United States, 79601

Texas Health Harris Methodist Hospital

Fort Worth, Texas, United States, 76104

Texas Health Hospital Frisco

Frisco, Texas, United States, 75033

Houston Methodist Hospital

Houston, Texas, United States, 77030

Sponsors and Collaborators

NeuroRx, Inc.

Lavin Consulting, LLC

Investigators

• Study Chair: Jonathan C Javitt, MD, MPH; NeuroRx, Inc.

More Information

• Responsible Party: NeuroRx, Inc.
• ClinicalTrials.gov Identifier: NCT04311697
• Other Study ID Numbers: COVID-AIV
• First Posted: March 17, 2020
• Last Update Posted: September 13, 2021
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: NeuroRx will share study protocol and statistical analysis plan upon request by qualified researchers
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Currently available
• Access Criteria: Public access

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by NeuroRx, Inc.:

COVID-19; ARDS; Aviptadil; Acute Respiratory Distress Syndrome; Respiratory Failure

Additional relevant MeSH terms:

COVID-19; Coronavirus Infections; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Respiratory Insufficiency; Acute Lung Injury; Lung Injury; Respiratory Tract Infections; Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Infant, Premature, Diseases; Infant, Newborn, Diseases; Thoracic Injuries; Wounds and Injuries; Phentolamine; Vasoactive Intestinal Peptide; Adrenergic alpha-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs