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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT04311697
Recruitment Status : Active, not recruiting
First Posted : March 17, 2020
Last Update Posted : December 29, 2020
Lavin Consulting, LLC
Information provided by (Responsible Party):
NeuroRx, Inc.

Tracking Information
First Submitted Date  ICMJE March 14, 2020
First Posted Date  ICMJE March 17, 2020
Last Update Posted Date December 29, 2020
Actual Study Start Date  ICMJE May 15, 2020
Estimated Primary Completion Date January 21, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 25, 2020)
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
Original Primary Outcome Measures  ICMJE
 (submitted: March 14, 2020)
  • Mortality [ Time Frame: 5 Days ]
  • PO2 [ Time Frame: 5 Days ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 25, 2020)
  • 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
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures
 (submitted: November 25, 2020)
  • 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
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Intravenous Aviptadil for Critical COVID-19 With Respiratory Failure
Official Title  ICMJE ZYESAMI (Aviptadil) for the Treatment of Critical COVID-19 With Respiratory Failure
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE 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
Condition  ICMJE
  • Critical COVID-19 With Respiratory Failure
  • Acute Respiratory Distress Syndrome (ARDS)
  • Corona Virus Infection
  • Acute Lung Injury
Intervention  ICMJE
  • 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
  • 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
Study Arms  ICMJE
  • 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
    Intervention: Drug: Aviptadil by intravenous infusion + standard of care
  • Experimental: Placebo + standard of care
    Patients will first be treated with placebo infusion + maximal intensive care
    Intervention: Drug: Normal Saline Infusion + standard of care
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: December 25, 2020)
Original Estimated Enrollment  ICMJE
 (submitted: March 14, 2020)
Estimated Study Completion Date  ICMJE February 28, 2021
Estimated Primary Completion Date January 21, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries Israel
Administrative Information
NCT Number  ICMJE NCT04311697
Other Study ID Numbers  ICMJE COVID-AIV
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Time Frame: Currently available
Access Criteria: Public access
Responsible Party NeuroRx, Inc.
Study Sponsor  ICMJE NeuroRx, Inc.
Collaborators  ICMJE Lavin Consulting, LLC
Investigators  ICMJE
Study Chair: Jonathan C Javitt, MD, MPH NeuroRx, Inc.
PRS Account NeuroRx, Inc.
Verification Date December 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP