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

COVID Clinical Trial

— AVICOVID-2  

Official title:

Inhaled ZYESAMI™ for the Treatment of Severe COVID-19

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04360096
• Other study ID #: RLF-100_002
• Status: Terminated
• Phase: Phase 2/Phase 3
• Start date: February 15, 2021
• Est. completion date: December 31, 2021

Study information

• Verified date: November 2021
• Source: APR Applied Pharma Research s.a.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 144
• Est. completion date: December 31, 2021
• Est. primary completion date: December 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Lung Injury
• Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS)
• ALI
• ARDS
• COVID
• Dyspnea
• Lung Injury
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Newborn
• SARS-CoV 2

Intervention

Drug:
• ZYESAMI™ (aviptadil acetate)
Inhaled ZYESAMI™ (aviptadil acetate) 100µg 3x daily by mesh nebulizer
• Placebo
Normal Saline Inhalation

Device:
• Nebulized administration of ZYESAMI™ or Placebo
Use of 510(k) cleared mesh nebulizer to deliver investigational product

Locations

Country	Name	City	State
United States	Doylestown Hospital	Doylestown	Pennsylvania
United States	St. Jude Medical Center	Fullerton	California
United States	Self Regional Healthcare	Greenwood	South Carolina
United States	University of California - Irvine	Irvine	California
United States	Kettering Health Network	Kettering	Ohio
United States	University Medical Center	Las Vegas	Nevada
United States	University of Louisville Hospital	Louisville	Kentucky
United States	University of Miami Leonard M. Miller School of Medicine (UMMSM)	Miami	Florida
United States	Great Plains Health	North Platte	Nebraska
United States	Advent Health Research Institute	Orlando	Florida
United States	University of Texas San Antonio Medical Arts and Research Center	San Antonio	Texas
United States	Holy Name Medical Center	Teaneck	New Jersey
United States	Northwestern Medical Group	Winfield	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
APR Applied Pharma Research s.a.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression to Respiratory Failure	Progression to Respiratory Failure is defined as the need for mechanical ventilation, non-invasive ventilation or high flow nasal oxygen	28 days
Secondary	Blood oxygenation	Blood PO2 as measured by pulse oximetry	28 days
Secondary	RPD Dyspnea Scale	0 = no shortness of breath at all 0.5 = very, very slight shortness of breath; = very mild shortness of breath; = mild shortness of breath; = moderate shortness of breath or breathing difficulty; = somewhat severe shortness of breath; = 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
Secondary	Distance walked in six minutes	Distance walked in six minutes	28 days

External Links

•   Javitt JC: Perspective: The potential role of vasoactive intestinal peptide in treating COVID-19
•   Pathogenesis of COVID-19 from a cell biologic perspective