Inhaled ZYESAMI™ (Aviptadil Acetate) for the Treatment of Severe COVID-19 (AVICOVID-2)

November 30, 2021 updated by: NeuroRx, Inc.

Inhaled ZYESAMI™ for the Treatment of Severe COVID-19

Brief Summary:

SARS-CoV-2 virus infection is known to cause Lung Injury that begins as dyspnea and exercise intolerance, but may rapidly progress to Critical COVID-19 with Respiratory Failure and the need for noninvasive or mechanical ventilation. Mortality rates as high as 80% have been reported among those who require mechanical ventilation, despite best available intensive care.

Patients with severe COVID-19 by FDA definition who have not developed respiratory failure be treated with nebulized ZYESAMI™ (aviptadil acetate, a synthetic version of Vasoactive Intestinal Polypeptide (VIP)) 100 μg 3x daily plus Standard of Care vs. placebo + Standard of Care using an FDA 501(k) cleared mesh nebulizer.

The primary outcome will be progression in severity of COVID-19 (i.e. critical OR severe progressing to critical) over 28 days. Secondary outcomes will include blood oxygenation as measured by pulse oximetry, dyspnea, exercise tolerance, and levels of TNFα IL-6 and other cytokines.

Study Overview

Detailed Description

Detailed Description:

Attack of the Alveolar Type II (ATII) cell via its ACE2 surface receptor by the SARS-CoV-2 virus leads to respiratory failure, morbidity, and frequently mortality in COVID-19. There is no approved treatment that specifically targets the pulmonary injury. Vasoactive Intestinal Peptide (VIP) is known to target the VPAC1 receptor of the ATII cell and to protect that cell against all manner of injuries, including smoke inhalation, exposure to stomach acid, and exposure to infectious agents. VIP prevents apoptosis, blocks cytokines, lowers TNFα levels, reverses CD4/CD8 ratio, and reduces cough and dyspnea in nonclinical and clinical studies. Aviptadil acetate, a synthetic form of Vasoactive Intestinal Polypeptide (VIP) has been awarded FDA Orphan Drug Designation for the treatment of ARDS and Pulmonary Hypertension and EMEA Orphan Drug Designation for the treatment of ARDS and Sarcoid. ZYESAMI™ (Aviptadil) has been granted FDA Fast Track Designation for the treatment of ARDS/Acute Lung Injury in COVID-19.

The objective of this study is to identify patients severe COVID-19 who have not yet developed respiratory failure and to treat them with inhaled ZYESAMI™ in the hope of preventing progression to Critical COVID-19 with Respiratory Failure.

Nonclinical studies demonstrate that VIP is 70% concentrated in the lung, where it binds primarily to ATII cells. VIP prevents NMDA-induced caspase-3 activation in the lung, inhibits IL6 and TNFα production, protects against HCl-induced pulmonary edema, 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.

Both intravenous and inhalation preclinical toxicology and safety pharmacology have been performed in four species, with a six-month trial of inhaled Aviptadil in primates.

Aviptadil is approved for human use in the treatment of erectile dysfunction in Scandinavia and several European countries in co-formulation with phentolamine and has a demonstrated phase 2 safety in trials for Sarcoid, Pulmonary Fibrosis, and Bronchospasm. No adverse safety signals were seen in a phase I trial IV Aviptadil 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.

A 60-day phase 2b/3 trial of IV Aviptadil (NCT 04311697) has recently completed enrollment and 28-day top-line safety data have been reported. No unanticipated serious adverse events were reported. The only adverse event that was statistically more frequent in Aviptadil-treated participants than among placebo-treated participants was mild to moderate diarrhea, which has not been reported as a frequent side-effect of inhaled Aviptadil (30% vs 1.5%; p< .001). Systemic hypotension was seen in both Aviptadil-treated and placebo-treated participants (25% vs 18.5%; P=NS).

Five GCP phase 2 trials of Aviptadil were conducted under European regulatory authority. Non GCP 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 with severe COVID-19 by FDA definition who have not developed respiratory failure will be treated with nebulized ZYESAMI™ 100 μg in 1 cc normal saline 3x daily plus Standard of Care vs. placebo + Standard of Care using an FDA 501(k) cleared mesh nebulizer.

The primary outcome will be progression to in severity of COVID-19 (i.e. critical OR severe progressing to critical) over 28 days. Secondary outcomes will include blood oxygenation as measured by pulse oximetry, dyspnea, exercise tolerance, and levels of TNFα IL-6 and other cytokines.

Study Type

Interventional

Enrollment (Anticipated)

144

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

    • California
      • Fullerton, California, United States, 92835
      • Irvine, California, United States, 92697
        • Recruiting
        • University of California - Irvine
        • Contact:
        • Principal Investigator:
          • Richard Lee, MD
    • Florida
      • Miami, Florida, United States, 33136
        • Recruiting
        • University of Miami Leonard M. Miller School of Medicine (UMMSM)
        • Contact:
        • Contact:
        • Principal Investigator:
          • Dushyantha Jayaweera, MD
      • Orlando, Florida, United States, 32803
        • Recruiting
        • Advent Health Research Institute
        • Contact:
        • Principal Investigator:
          • Amay Parikh, MD
    • Illinois
      • Winfield, Illinois, United States, 60190
        • Recruiting
        • Northwestern Medical Group
        • Contact:
        • Principal Investigator:
          • Luis Manrique, MD
    • Kentucky
      • Louisville, Kentucky, United States, 40202
    • Nebraska
      • North Platte, Nebraska, United States, 69101
        • Recruiting
        • Great Plains Health
        • Contact:
          • Cynthia Brady
          • Phone Number: 308-568-3651
        • Contact:
          • bradycj@gphealth.org
        • Principal Investigator:
          • Eduardo Freitas, MD
    • Nevada
      • Las Vegas, Nevada, United States, 89102
        • Recruiting
        • University Medical Center
        • Principal Investigator:
          • Shadaba Asad, MD
    • New Jersey
      • Teaneck, New Jersey, United States, 07666
        • Recruiting
        • Holy Name Medical Center
        • Contact:
        • Principal Investigator:
          • Suraj Saggar, MD
    • Ohio
      • Kettering, Ohio, United States, 45429
    • Pennsylvania
      • Doylestown, Pennsylvania, United States, 18901
        • Recruiting
        • Doylestown Hospital
        • Contact:
        • Principal Investigator:
          • Les Szekely, MD
    • South Carolina
      • Greenwood, South Carolina, United States, 29646
        • Recruiting
        • Self Regional Healthcare
        • Contact:
        • Principal Investigator:
          • John Tejada, MD
    • Texas
      • San Antonio, Texas, United States, 78229
        • Recruiting
        • University of Texas San Antonio Medical Arts and Research Center
        • Principal Investigator:
          • Thomas Patterson, MD
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 83 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion criteria:

  1. Severe COVID-19 , as defined by clinical signs indicative of severe systemic illness with COVID-19, being given oxygenation and meeting

    ONE of the following:

    Respiratory rate ≥ 30 per minute Heart rate ≥ 125 per minute SpO2 ≤ 93% on room air at sea level PaO2/FiO2 < 300 mmHg or SpO2/FiO2 < 315 mmHg

  2. Positive test by standard RT-PCR assay or equivalent within last 7 days
  3. Physician determination that patient is on SOC therapy, and will receive standard of care if patient progresses to Critical COVID-19, patient must be full CODE

Exclusion criteria:

  1. Evidence of Critical COVID-19
  2. Inability to utilize nebulized drugs, or history of bronchospasm with inhaled medications
  3. Age <12 years;
  4. Mean arterial pressure < 65 mm Hg after initial hospital stabilization,
  5. Non-COVID-19 irreversible underlying condition with projected fatal course within 6 months or with high risk of mortality;
  6. Immunosuppressive treatment for transplant or other diseases associated with high mortality;
  7. Stage IV cancer or cancer on active treatment with chemotherapy immunotherapy or checkpoint inhibitors; acute renal failure or chronic renal insufficiency with GFR less than 30; CHF New York Heart Association class III or IV, new neurologic disorder in the last 3 months or chronic neurologic disorder or other that would impact on assessing the resolution of severe COVID-19 respiratory failure
  8. Myocardial Infarction in previous six months or troponin >0.5
  9. Recent history of venous thrombotic events (PE / DVT) within the last 3 months.
  10. New diagnosis of atrial fibrillation within the last 3 months. Acceptable if greater than 3 months and well controlled in the opinion of the investigator
  11. Watery diarrhea requiring replacement of 1 liter or more of iv fluids and electrolytes
  12. Pregnancy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Severe COVID-19 ZYESAMI™
Patients with Severe COVID-19 to be treated with inhaled ZYESAMI™ (aviptadil) by mesh nebulizer 100μg 3x daily
Inhaled ZYESAMI™ (aviptadil acetate) 100μg 3x daily by mesh nebulizer
Use of 510(k) cleared mesh nebulizer to deliver investigational product
Experimental: Severe COVID-19 Placebo
Patients with Severe COVID-19 to be treated with inhaled placebo 3x daily
Use of 510(k) cleared mesh nebulizer to deliver investigational product
Normal Saline Inhalation

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression to Respiratory Failure
Time Frame: 28 days
Progression to Respiratory Failure is defined as the need for mechanical ventilation, non-invasive ventilation or high flow nasal oxygen
28 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Blood oxygenation
Time Frame: 28 days
Blood PO2 as measured by pulse oximetry
28 days
RPD Dyspnea Scale
Time Frame: 28 days

0 = no shortness of breath at all 0.5 = very, very slight shortness of breath

  1. = very mild shortness of breath
  2. = mild shortness of breath
  3. = moderate shortness of breath or breathing difficulty
  4. = somewhat severe shortness of breath
  5. = strong or hard breathing

7 = severe shortness of breath or very hard breathing 8 9 = extremely severe shortness of breath 10 = shortness of breath so severe you need to stop the exercise or activity

28 days
Distance walked in six minutes
Time Frame: 28 days
Distance walked in six minutes
28 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Investigators

  • Study Chair: Jonathan C Javitt, MD, MPH, NeuroRx

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 15, 2021

Primary Completion (Anticipated)

December 15, 2021

Study Completion (Anticipated)

December 31, 2021

Study Registration Dates

First Submitted

April 21, 2020

First Submitted That Met QC Criteria

April 22, 2020

First Posted (Actual)

April 24, 2020

Study Record Updates

Last Update Posted (Actual)

December 1, 2021

Last Update Submitted That Met QC Criteria

November 30, 2021

Last Verified

November 1, 2021

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Sharing Supporting Information Type

  • Study Protocol
  • Statistical Analysis Plan (SAP)
  • Informed Consent Form (ICF)
  • Clinical Study Report (CSR)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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