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

• ClinicalTrials.gov Identifier: NCT04360096
• Recruitment Status: Recruiting
• First Posted: April 24, 2020
• Last Update Posted: December 1, 2021
• Sponsor: NeuroRx, Inc.
• Information provided by (Responsible Party): NeuroRx, Inc.

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
SARS-CoV 2; COVID; ARDS; ALI; Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS); Dyspnea	Drug: ZYESAMI™ (aviptadil acetate); Drug: Placebo; Device: Nebulized administration of ZYESAMI™ or Placebo	Phase 2; Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 144 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Multicenter Randomized Placebo-controlled Trial
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Only the study pharmacist will be aware of treatment assignment
• Primary Purpose: Treatment
• Official Title: Inhaled ZYESAMI™ for the Treatment of Severe COVID-19
• Actual Study Start Date: February 15, 2021
• Estimated Primary Completion Date: December 15, 2021
• Estimated Study Completion Date: December 31, 2021

Arms and Interventions

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	Drug: ZYESAMI™ (aviptadil acetate); Inhaled ZYESAMI™ (aviptadil acetate) 100μg 3x daily by mesh nebulizer; Device: Nebulized administration of ZYESAMI™ or Placebo; 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	Drug: Placebo; Normal Saline Inhalation; Device: Nebulized administration of ZYESAMI™ or Placebo; Use of 510(k) cleared mesh nebulizer to deliver investigational product

Outcome Measures

Primary Outcome Measures :

1. 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

Secondary Outcome Measures :

1. Blood oxygenation [ Time Frame: 28 days ]
   Blood PO2 as measured by pulse oximetry
2. 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

3. Distance walked in six minutes [ Time Frame: 28 days ]
   Distance walked in six minutes

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Robert E Besthof, MIM; +48425461134; rbesthof@neurorxpharma.com

Locations

United States, California

St. Jude Medical Center; Recruiting

Fullerton, California, United States, 92835

Contact: Linda Gozar Linda.Gozar@stjoe.org

Principal Investigator: David Park, MD

University of California - Irvine; Recruiting

Irvine, California, United States, 92697

Contact: Rosie Magallon rmagallo@hs.uci.edu

Principal Investigator: Richard Lee, MD

United States, Florida

University of Miami Leonard M. Miller School of Medicine (UMMSM); Recruiting

Miami, Florida, United States, 33136

Contact: Mayra Vidro 305-243-7047 mvidro@med.miami.edu

Contact: Russell Saltzman 305 243 1152 r.saltzman@med.miami.edu

Principal Investigator: Dushyantha Jayaweera, MD

Advent Health Research Institute; Recruiting

Orlando, Florida, United States, 32803

Contact: Mariam Lobbous 407-303-5915 mariam.lobbous@adventhealth.com

Principal Investigator: Amay Parikh, MD

United States, Illinois

Northwestern Medical Group; Recruiting

Winfield, Illinois, United States, 60190

Contact: Sarah Madia 630-933-5281 sarah.madia@nm.org

Principal Investigator: Luis Manrique, MD

United States, Kentucky

University of Louisville Hospital; Recruiting

Louisville, Kentucky, United States, 40202

Contact: Elizabeth Cooke Elizabetha.cooke@louisville.edu

Principal Investigator: Rainer Lenhardt, MD

United States, Nebraska

Great Plains Health; Recruiting

North Platte, Nebraska, United States, 69101

Contact: Cynthia Brady 308-568-3651

Contact: bradycj@gphealth.org

Principal Investigator: Eduardo Freitas, MD

United States, Nevada

University Medical Center; Recruiting

Las Vegas, Nevada, United States, 89102

Contact: jennifer robinson 702-383-7842 jennifer.robinson@umcsn.com

Principal Investigator: Shadaba Asad, MD

United States, New Jersey

Holy Name Medical Center; Recruiting

Teaneck, New Jersey, United States, 07666

Contact: Patty Kiledjian pkiledjian@holyname.org

Principal Investigator: Suraj Saggar, MD

United States, Ohio

Kettering Health Network; Recruiting

Kettering, Ohio, United States, 45429

Contact: Daniel Geyer daniel.geyer@ketteringhealth.org

Principal Investigator: Jeffery Weinstein, MD

United States, Pennsylvania

Doylestown Hospital; Recruiting

Doylestown, Pennsylvania, United States, 18901

Contact: Teresa Mannion 215-345-2842 tmannion@dh.org

Principal Investigator: Les Szekely, MD

United States, South Carolina

Self Regional Healthcare; Recruiting

Greenwood, South Carolina, United States, 29646

Contact: erin smith 864-725-1967 Erin.Smith@selfregional.org

Principal Investigator: John Tejada, MD

United States, Texas

University of Texas San Antonio Medical Arts and Research Center; Recruiting

San Antonio, Texas, United States, 78229

Contact: Robin Tragus 210-567-5262 tragus@uthscsa.edu

Principal Investigator: Thomas Patterson, MD

Sponsors and Collaborators

NeuroRx, Inc.

Investigators

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

More Information

Additional Information:

Javitt JC: Perspective: The potential role of vasoactive intestinal peptide in treating COVID-19 

Pathogenesis of COVID-19 from a cell biologic perspective 

• Responsible Party: NeuroRx, Inc.
• ClinicalTrials.gov Identifier: NCT04360096
• Other Study ID Numbers: RLF-100_002
• First Posted: April 24, 2020
• Last Update Posted: December 1, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes

Keywords provided by NeuroRx, Inc.:

Corona Virus; VIP; Aviptadil; Vasoactive Intestinal Polypeptide

Additional relevant MeSH terms:

Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Dyspnea; Lung Injury; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Infant, Premature, Diseases; Infant, Newborn, Diseases; Signs and Symptoms, Respiratory; Thoracic Injuries; Wounds and Injuries