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

  • STATUS
    Recruiting
  • End date
    Dec 31, 2021
  • participants needed
    144
  • sponsor
    NeuroRx, Inc.
Updated on 17 September 2021
mechanical ventilation
cytokines
FIO2
respiratory failure
pao2
covid-19
SARS
assisted breathing

Summary

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 g 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 TNF IL-6 and other cytokines.

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 TNF 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 TNF 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 g 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 TNF IL-6 and other cytokines.

Details
Condition Acute Lung Injury, Dyspnea, ADULT RESPIRATORY DISTRESS SYNDROME, Acute Respiratory Distress Syndrome (ARDS), COVID-19, COVID-19, Coronavirus Disease (COVID-19), COVID-19, COVID-19, Pathogen Infection Covid-19 Infection, *Corona Virus Infection, *COVID-19 Infection, Corona Virus Disease 2019(COVID-19), COVID-19, COVID-19, Treat and Prevent Covid-19 Infection, COVID-19, COVID-19 Infection, *COVID-19, COVID-19, Covid-19, COVID-19, COVID-19 Pneumonia, COVID-19, COVID-19, COVID-19, Covid-19, Pathogen Infection Covid-19 Infection, COVID-19, COVID-19, COVID-19, Use of Stem Cells for COVID-19 Treatment, COVID-19, COVID-19, Hospitalized Patients With Covid-19 Pneumonia, Corona Virus Disease 2019(COVID-19), COVID-19 Pneumonia, COVID-19; Cardiovascular Diseases, Community-acquired Pneumonia, Influenza, COVID-19, Old Age, Usability, Visio Telephony, Confinement, Covid-19, COVID-19 Pneumonia, COVID-19 Pneumonia, Acute Respiratory Distress Syndrome Caused by COVID-19, COVID-19 Pneumonia, Corona Virus Disease 2019(COVID-19), Old Age, Usability, Visio Telephony, Confinement, Covid-19, SARS-CoV-2 (COVID-19) Infection, COVID-19 Pneumonia, Corona Virus Disease 2019(COVID-19), COVID-19 Pneumonia, Severe Coronavirus Disease (COVID-19), Acute Respiratory Distress Syndrome Caused by COVID-19, COVID-19 Pneumonia, COVID-19, Hydroxychloroquine Sulfate, SARS-CoV-2 (COVID-19) Infection, COVID-19 Pneumonia, COVID-19, Hydroxychloroquine Sulfate, Anxiety Related to the COVID-19 Pandemic, Acute Respiratory Distress Syndrome Caused by COVID-19, Severe Coronavirus Disease (COVID-19), COVID-19 Pneumonia, *COVID-19 Infection, Severe Coronavirus Disease (COVID-19), COVID-19 by SARS-CoV-2 Infection, ALI, breathlessness, shortness of breath, breathing difficulty, difficulty breathing, breathless, trouble breathing, respiratory difficulties, breathing difficulties, acute respiratory distress syndrome, ards, Sars Cov 2, Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS)
Treatment Placebo, RLF-100 (aviptadil), Nebulized administration of RLF-100 or Placebo, ZYESAMI™ (aviptadil acetate), Nebulized administration of ZYESAMI™ or Placebo
Clinical Study IdentifierNCT04360096
SponsorNeuroRx, Inc.
Last Modified on17 September 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

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
\. Positive test by standard RT-PCR assay or equivalent within last 7 days
\. 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

Evidence of Critical COVID-19
Inability to utilize nebulized drugs, or history of bronchospasm with inhaled medications
Age <12 years
Mean arterial pressure < 65 mm Hg after initial hospital stabilization
Non-COVID-19 irreversible underlying condition with projected fatal course within 6 months or with high risk of mortality
Immunosuppressive treatment for transplant or other diseases associated with high mortality
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
Myocardial Infarction in previous six months or troponin >0.5
Recent history of venous thrombotic events (PE / DVT) within the last 3 months
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
Watery diarrhea requiring replacement of 1 liter or more of iv fluids and electrolytes
Pregnancy
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