ZYESAMI (Aviptadil) Intermediate Population Expanded Access Protocol (SAMICARE)
ZYESAMI (Aviptadil) Intermediate Population Expanded Access Protocol (SAMICARE)
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
 https://www.fda.gov/media/91160/download
5. INTRODUCTION

 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. OBJECTIVES

 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.
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

 -  ECMO

 -  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