Intravenous Aviptadil for Critical COVID-19 With Respiratory Failure
Condition: Critical COVID-19 With Respiratory Failure; Acute Respiratory Distress Syndrome (ARDS); Corona Virus Infection; Acute Lung Injury
MeSH terms: COVID-19; Coronavirus Infections; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Respiratory Insufficiency; Acute Lung Injury; Lung Injury
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Intervention name(s): Aviptadil by intravenous infusion + standard of care; Normal Saline Infusion + standard of care
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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 intervention name(s): ZYESAMI (aviptadil) +SOC; Placebo+SOC
Intervention MeSH terms: Phentolamine; Vasoactive Intestinal Peptide
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)
Primary purpose: Treatment
Keywords: COVID-19; ARDS; Aviptadil; Acute Respiratory Distress Syndrome; Respiratory Failure