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History of Changes for Study: NCT04311697
Intravenous Aviptadil for Critical COVID-19 With Respiratory Failure (COVID-AIV)
Latest version (submitted February 23, 2021) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 March 14, 2020 None (earliest Version on record)
2 March 16, 2020 Contacts/Locations, Outcome Measures and Study Status
3 March 23, 2020 Arms and Interventions, Contacts/Locations, Outcome Measures, Study Description and Study Status
4 March 24, 2020 Study Design, Arms and Interventions, Outcome Measures, Study Description, Contacts/Locations and Study Status
5 April 1, 2020 Contacts/Locations, Oversight, Sponsor/Collaborators and Study Status
6 April 3, 2020 Contacts/Locations and Study Status
7 April 8, 2020 Contacts/Locations, Oversight and Study Status
8 April 21, 2020 Contacts/Locations, Study Description and Study Status
9 May 15, 2020 Recruitment Status, Study Status, Contacts/Locations, Study Design and Study Description
10 June 1, 2020 Recruitment Status, Contacts/Locations, Study Status, Conditions and Study Description
11 June 2, 2020 Arms and Interventions, Conditions, Study Description, Study Identification, Eligibility and Study Status
12 June 30, 2020 IPDSharing, Sponsor/Collaborators, Study Status and Contacts/Locations
13 July 27, 2020 Study Status
14 August 27, 2020 Contacts/Locations, Outcome Measures and Study Status
15 October 29, 2020 Study Status
16 November 25, 2020 Outcome Measures, Study Status, IPDSharing, Arms and Interventions, Study Design, Sponsor/Collaborators and Study Identification
17 December 25, 2020 Recruitment Status, Study Status, Study Design, Contacts/Locations, Arms and Interventions, Study Description and Study Identification
18 January 27, 2021 Contacts/Locations and Study Status
19 January 28, 2021 Contacts/Locations and Study Status
20 February 16, 2021 Study Status and Outcome Measures
21 February 23, 2021 Recruitment Status, Study Status and Outcome Measures
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Changes (Merged) for Study: NCT04311697
February 16, 2021 (v20) -- February 23, 2021 (v21)

Changes in: Study Status and Outcome Measures

Open or close this module Study Identification
Unique Protocol ID: COVID-AIV
Brief Title: Intravenous Aviptadil for Critical COVID-19 With Respiratory Failure (COVID-AIV)
Official Title: ZYESAMI (Aviptadil) for the Treatment of Critical COVID-19 With Respiratory Failure
Secondary IDs:
Open or close this module Study Status
Record Verification: February 2021
Overall Status: Active, not recruiting Completed
Study Start: May 15, 2020
Primary Completion: January 21 February 22, 2021 [Actual]
Study Completion: February 28 22, 2021 [ Anticipated Actual]
First Submitted: March 14, 2020
First Submitted that
Met QC Criteria:
March 14, 2020
First Posted: March 17, 2020 [Actual]
Last Update Submitted that
Met QC Criteria:
February 16 23, 2021
Last Update Posted: February 18 26, 2021 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: NeuroRx, Inc.
Responsible Party: Sponsor
Collaborators: Lavin Consulting, LLC
Open or close this module Oversight
U.S. FDA-regulated Drug: Yes
U.S. FDA-regulated Device: No
Data Monitoring: Yes
Open or close this module 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.
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.

Open or close this module Conditions
Conditions: Critical COVID-19 With Respiratory Failure
Acute Respiratory Distress Syndrome (ARDS)
Corona Virus Infection
Acute Lung Injury
Keywords: COVID-19
ARDS
Aviptadil
Acute Respiratory Distress Syndrome
Respiratory Failure
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 2/Phase 3
Interventional Study Model: Parallel Assignment
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
Number of Arms: 2
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation: Randomized
Enrollment: 196 [Actual]
Open or close this module Arms and Interventions
Arms Assigned Interventions
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
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Resolution of Respiratory Failure (Composite Endpoint)
Cumulative distribution of the time to respiratory failure resolution (without relapse over 7 days) with concurrent survival through day 28

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

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

[Time Frame: Day 0 through day 28 (interim) and 60]
4. Time to ICU discharge
Time to discharge from Intensive Care Unit

[Time Frame: Day 0 through day 28 (interim) and 60]
5. Time on ventilation
Time on mechanical ventilation, non-invasive ventilation, or high-flow nasal oxygen

[Time Frame: Day 0 through day 28 (interim) and 60]
6. Time to extubation
Time to extubation (for those initially on mechanical ventilation)

[Time Frame: Day 0 through day 28 (interim) and 60]
7. Time to discharge alive
Time to discharge alive

[Time Frame: Day 0 through day 28 (interim) and day 60]
8. Multi-organ failure free days
Days free of multisystem organ failure

[Time Frame: Day 0 through day 28 (interim) and 60]
Other Pre-specified Outcome Measures:
9. Respiratory Distress while on mechanical ventilation
PaO2:FiO2 ratio

[Time Frame: Day 0 through day 28 (interim) and 60]
10. Oxygenation index
Oxygenation index

[Time Frame: Day 0 through day 28 (interim) and 60]
11. Improvement in chest x-ray
Improvement in chest x-ray by RALES score

[Time Frame: Day 0 through day 28 (interim) and 60]
12. Improvement in inflammatory markers
Improvement in IL-6, TNF alpha, and other inflammatory markers

[Time Frame: Day 0 through day 28 (interim) and 60]
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age: 100 Years
Sex: All
Gender Based:
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
Open or close this module Contacts/Locations
Study Officials: Jonathan C Javitt, MD, MPH
Study Chair
NeuroRx, Inc.
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
Open or close this module IPDSharing
Plan to Share IPD: Yes
NeuroRx will share study protocol and statistical analysis plan upon request by qualified researchers
Supporting Information:
Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame:
Currently available
Access Criteria:
Public access
URL:
Open or close this module References
Citations:
Links:
Available IPD/Information:

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