Inhaled ZYESAMI™ (Aviptadil Acetate) for the Treatment of Severe COVID-19 (AVICOVID-2)
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ClinicalTrials.gov Identifier: NCT04360096 |
Recruitment Status :
Recruiting
First Posted : April 24, 2020
Last Update Posted : December 1, 2021
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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 |
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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 |

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 |

Arm | Intervention/treatment |
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Experimental: Severe COVID-19 ZYESAMI™
Patients with Severe COVID-19 to be treated with inhaled ZYESAMI™ (aviptadil) by mesh nebulizer 100μg 3x daily
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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
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Drug: Placebo
Normal Saline Inhalation Device: Nebulized administration of ZYESAMI™ or Placebo Use of 510(k) cleared mesh nebulizer to deliver investigational product |
- 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
- Blood oxygenation [ Time Frame: 28 days ]Blood PO2 as measured by pulse oximetry
- RPD Dyspnea Scale [ Time Frame: 28 days ]
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
- Distance walked in six minutes [ Time Frame: 28 days ]Distance walked in six minutes

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Ages Eligible for Study: | 18 Years to 85 Years (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion criteria:
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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
- Positive test by standard RT-PCR assay or equivalent within last 7 days
- 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:
- Evidence of Critical COVID-19
- Inability to utilize nebulized drugs, or history of bronchospasm with inhaled medications
- Age <12 years;
- Mean arterial pressure < 65 mm Hg after initial hospital stabilization,
- Non-COVID-19 irreversible underlying condition with projected fatal course within 6 months or with high risk of mortality;
- Immunosuppressive treatment for transplant or other diseases associated with high mortality;
- 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
- Myocardial Infarction in previous six months or troponin >0.5
- Recent history of venous thrombotic events (PE / DVT) within the last 3 months.
- 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
- Watery diarrhea requiring replacement of 1 liter or more of iv fluids and electrolytes
- Pregnancy

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04360096
Contact: Robert E Besthof, MIM | +48425461134 | rbesthof@neurorxpharma.com |
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 |
Study Chair: | Jonathan C Javitt, MD, MPH | NeuroRx |
Responsible Party: | NeuroRx, Inc. |
ClinicalTrials.gov Identifier: | NCT04360096 |
Other Study ID Numbers: |
RLF-100_002 |
First Posted: | April 24, 2020 Key Record Dates |
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 |
Corona Virus VIP Aviptadil Vasoactive Intestinal Polypeptide |
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 |