Official Title
ZYESAMI (Aviptadil) Intermediate Population Expanded Access Protocol
Brief Summary

Patients with Critical COVID-19 and respiratory failure who are ineligible for enrollment in NCT04311697, who live more than 50 miles from an existing collaborating research center, or who are already hospitalized and cannot safely be transferred to a collaborating research facility may be considered for expanded access by the sponsor. Treating physicians must complete FDA Form 3396 and receive a letter of authorization from NeuroRx, along with local IRB authorization. Please refer to FDA guidance for Individual Patient Expanded Access

Detailed Description


5.1 Executive Summary ZYESAMI (aviptadil) is a synthetic form of Vasoactive Intestinal
Polypeptide (VIP), a ubiquitous, naturally synthesized human peptide with extensively
documented anti-inflammatory, anti-cytokine cascade properties. It has been granted FDA Fast
Track Designation for treatment of Critical COVID-19 with Respiratory Failure. A phase 2/3
trial is underway that has passed its first evaluation at 30 patients for safety and
futility. This expanded access protocol is designed to offer access to investigational use of
RLF-100 to patients who do not qualify for inclusion in Protocol RLF-100-001 (NCT04311697)
either on the basis of specific medical exclusions or because there is no accessible study
site available to the prospective participant.

5.2 Definition of Critical COVID-19

In May 2020, FDA defined Critical COVID-19 to be used in clinical trials and disease staging
as follows:

Critical COVID-19

- Positive testing by standard RT-PCR assay or an equivalent test

- Evidence of Respiratory Failure based on FDA definition of: need for Endotracheal
intubation and mechanical ventilation, oxygen delivered by high-flow nasal cannula
(heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates > 20
L/min with fraction of delivered oxygen ≥ 0.5), noninvasive positive pressure
ventilation, ECMO, or clinical diagnosis of respiratory failure (i.e., clinical need for
one of the preceding therapies, but preceding therapies not able to be administered in
setting of resource limitation)

Acute Lung Injury in COVID-19 is characterized by progressive failure of corporeal
oxygenation, attributed on large part by SARS-CoV-2 infection of Alveolar Type II cells
(Mason 2020). Extensive nonclinical studies document that 70% of VIP in the body binds to
receptors on the Alveolar Type II cell, where VIP is known to block cytokine production and
upregulate production of surfactant.

Severity of COVID is associated with and graded by a progressively worsened state of
oxygenation. This is seen in the PaO2/FIO2 ratio, which reflects the status of oxygenation
for patients on high pressure oxygen and mechanical ventilation. In patients breathing room
air, disease severity is assessed by SpO2. Many patients with Critical COVID meet the
clinical definitions of Acute Respiratory Distress Syndrome (ARDS). However, there is
increasing recognition that respiratory distress in COVID-19 has different characteristics
than ARDS in the setting of bacterial sepsis and other common presentations of ARDS.

The pathologic hallmark of COVID-19 lung injury is diffuse alveolar damage, vascular
endothelium damage, and damage to the surfactant-producing type II cells which results in
loss of the integrity of the alveolar-capillary barrier, transudation of protein-rich fluid
across the barrier, pulmonary edema, and hypoxemia from intrapulmonary shunting. Typically,
patients who have progressed to Critical COVID-19 require care in an intensive care unit
(ICU). The mortality rate is approximately 50%. Deaths usually result from multisystem organ
failure rather than lung failure alone.

5.3 ZYESAMI Experimental Therapy in COVID-19

Under this protocol, patients with Critical COVID-19 will be treated with ZYESAMI (Aviptadil)
with the aim to support pulmonary alveolar function, combat the cytokine-induced
inflammation, improve blood oxygenation, and reduce mortality.

5.4 Clinical Rationale Given by intravenous infusion in appropriate concentrations, ZYESAMI
has been shown in clinical trials to have a manageable safety profile with no observed SAEs
to date that would rise to the level of a black box warning.


6.1 Primary Objective The primary objective of this study is to measure the effectiveness and
safety of ZYESAMI + maximal standard of care (SOC) in treating Critical COVID-19 with
Respiratory Failure.

6.2 Secondary Objective The key secondary objective is to test the hypothesis that ZYESAMI
improves blood oxygenation as measured by SaO2.

No longer available
Intermediate-size Population
Critical COVID-19 With Respiratory Failure

Drug: ZYESAMI (aviptadil acetate)

Patients will be treated with 12 hour infusions of ZYESAMI at ascending doses of 50/100/150 pmol/kg/hr on 3 or more successive days
Other Name: Array

Eligibility Criteria

Inclusion Criteria:

- Critical COVID-19 with Respiratory Failure

Exclusion Criteria:

- Patients who are eligible for enrollment in RLF-100_001 are excluded from this
protocol and live within 50 miles of a study site for NCT04311697 cannot be enrolled
unless already admitted to an ICU and ineligible for transfer

- Mean Arterial Pressure < 65 mm Hg with use of pressor per ICU protocol

- Irreversible condition (other than COVID-19) with projected fatal course


- Chemotherapy-induced neutropenia (granulocyte count <1000/mm3);

- Cardiogenic shock; congestive heart failure - NYHA Class 3 or 4;

- Liquid Diarrhea more than 3x/day; defined as more than 3 non-bloody watery stools
within a 24-hour period, requiring additional fluid and electrolyte supplementation

Eligibility Gender
Eligibility Age
Minimum: 12 Years ~ Maximum: 100 Years
United States

Dignity Health-Mercy Gilbert Medical Center
Gilbert, Arizona, United States

Honor Health Shea Medical Center
Scottsdale, Arizona, United States

Kaiser Permanente
Baldwin Park, California, United States

University of California - Irvine
Irvine, California, United States

Lawnwood Regional Medical Center
Fort Pierce, Florida, United States

Lakeland Regional Health
Lakeland, Florida, United States

Miller School of Medicine / University of Miami Medical Center
Miami, Florida, United States

Baptist Hospital of Miami
Miami, Florida, United States

Baycare St. Joseph Hospital
Tampa, Florida, United States

Southeast Georgia Health system
Brunswick, Georgia, United States

Maui Health Systems
Wailuku, Hawaii, United States

St. Anthony Regional Hospital
Carroll, Iowa, United States

University of Louisville
Louisville, Kentucky, United States

St. Tammany Parish Hospital
Covington, Louisiana, United States

Our Ladies of Lourdes Regional Hospital
Lafayette, Louisiana, United States

St. Joseph Heritage Healthcare
Saint Joseph, Missouri, United States

Great Plains Health
North Platte, Nebraska, United States

Self Regional Healthcare
Greenwood, South Carolina, United States

Hendrick Medical Center
Abilene, Texas, United States

Baptist Hospitals of Southeast Texas
Beaumont, Texas, United States

Medical City Denton
Denton, Texas, United States

HR Health Institute for Research & Development
Edinburg, Texas, United States

Houston Methodist Hospital
Houston, Texas, United States

Memorial Hermann Hospital Houston
Houston, Texas, United States

Medical City McKinney
McKinney, Texas, United States

Jonathan C Javitt, MD, MPH, Study Chair
NRx Pharmaceuticals, Inc.

APR Applied Pharma Research s.a.
NCT Number
MeSH Terms
Respiratory Insufficiency
Vasoactive Intestinal Peptide