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

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ClinicalTrials.gov Identifier: NCT04311697
Recruitment Status : Completed
First Posted : March 17, 2020
Last Update Posted : February 26, 2021
Sponsor:
Collaborator:
Lavin Consulting, LLC
Information provided by (Responsible Party):
NeuroRx, Inc.

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 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.

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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


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




Primary Outcome Measures :
  1. Resolution of Respiratory Failure (Composite Endpoint) [ Time Frame: Day 0 through day 28 (interim) and 60 ]
    Cumulative distribution of the time to respiratory failure resolution (without relapse over 7 days) with concurrent survival through day 28


Secondary Outcome Measures :
  1. Improvement on NIAID Scale (key secondary measure) [ Time Frame: Day 0 through day 28 (interim) and 60 ]
    Achievement of score 6-8 on NIAID Ordinal Scale through day 28

  2. Survival through day 28 and day 60 [ Time Frame: Day 0 through day 28 (interim) and 60 ]
    Survival probability on Kaplan Meier lifetable through day 28 and 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 [ 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



Information from the National Library of Medicine

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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

Information from the National Library of Medicine

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


Locations
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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
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Study Chair: Jonathan C Javitt, MD, MPH NeuroRx, Inc.
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Responsible Party: NeuroRx, Inc.
ClinicalTrials.gov Identifier: NCT04311697    
Other Study ID Numbers: COVID-AIV
First Posted: March 17, 2020    Key Record Dates
Last Update Posted: February 26, 2021
Last Verified: February 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

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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:
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Coronavirus Infections
Severe Acute Respiratory Syndrome
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Respiratory Insufficiency
Acute Lung Injury
Lung Injury
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Virus Diseases
Thoracic Injuries
Wounds and Injuries
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Respiratory Tract Infections
Phentolamine
Vasoactive Intestinal Peptide
Adrenergic alpha-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antihypertensive Agents
Gastrointestinal Agents
Vasodilator Agents