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

• ClinicalTrials.gov Identifier: NCT04360096
• Recruitment Status: Recruiting
• First Posted: April 24, 2020
• Last Update Posted: April 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 moderate and 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 to in severity of COVID-19 (i.e. moderate progressing to severe or 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 with moderate and 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 moderate and 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. moderate progressing to severe or 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: 288 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 Moderate and Severe COVID-19
• Actual Study Start Date: February 15, 2021
• Estimated Primary Completion Date: August 15, 2021
• Estimated Study Completion Date: September 1, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Moderate COVID-19 ZYESAMI™; Patients with Moderate 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: Moderate COVID-19 Placebo; Patients with Moderate 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
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. RDP Dsypnea 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: 12 Years to 85 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Moderate or Severe COVID-19 by FDA definition with no evidence of Respiratory Failure
2. Capable of using mesh nebulizer to administer medication with assistance if needed

Exclusion Criteria:

1. Evidence of Respiratory Failure
2. Use or impending use of ventilation or high flow nasal oxygen 20L or greater

4) Age <12 years; 5) Diastolic pressure < 65 mm Hg; 6) Irreversible underlying condition with projected fatal course; 7) Immunosuppressive treatment for transplant or other reasons; 8) Cancer, renal failure, congestive heart failure, neurological disorder 9) Recent myocardial infarction with Troponin >0.5

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, Kentucky

University of Louisville Hospital; Recruiting

Louisville, Kentucky, United States, 40202

Contact: Elizabeth Cooke Elizabetha.cooke@louisville.edu

Principal Investigator: Rainer Lenhardt, 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: April 1, 2021
• Last Verified: March 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, Newborn; Respiratory Distress Syndrome, Adult; 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