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.
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.
Drug: ZYESAMI™ (aviptadil acetate)
Inhaled ZYESAMI™ (aviptadil acetate) 100μg 3x daily by mesh nebulizer
Drug: Placebo
Normal Saline Inhalation
Device: Nebulized administration of ZYESAMI™ or Placebo
Use of 510(k) cleared mesh nebulizer to deliver investigational product
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
St. Jude Medical Center
Fullerton, California, United States
University of California - Irvine
Irvine, California, United States
University of Miami Leonard M. Miller School of Medicine (UMMSM)
Miami, Florida, United States
Advent Health Research Institute
Orlando, Florida, United States
Northwestern Medical Group
Winfield, Illinois, United States
University of Louisville Hospital
Louisville, Kentucky, United States
Great Plains Health
North Platte, Nebraska, United States
University Medical Center
Las Vegas, Nevada, United States
Holy Name Medical Center
Teaneck, New Jersey, United States
Kettering Health Network
Kettering, Ohio, United States
Doylestown Hospital
Doylestown, Pennsylvania, United States
Self Regional Healthcare
Greenwood, South Carolina, United States
University of Texas San Antonio Medical Arts and Research Center
San Antonio, Texas, United States
Jonathan C Javitt, MD, MPH, Study Chair
NeuroRx