Clinical trial NCT04453839: ZYESAMI (Aviptadil) Intermediate Population Expanded Access Protocol (SAMICARE)
Official title: ZYESAMI (Aviptadil) Intermediate Population Expanded Access Protocol
Study type: EXPANDED_ACCESS
Overall status: NO_LONGER_AVAILABLE
Conditions: Critical COVID-19 With Respiratory Failure
Lead sponsor: APR Applied Pharma Research s.a.
Sponsor class: OTHER
First posted: 2020-07-01
Sex: ALL
Minimum age (years): 12
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT

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 https://www.fda.gov/media/91160/download

Detailed description: 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.

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
* 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

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Dignity Health-Mercy Gilbert Medical Center
state: Arizona
city: Scottsdale
country: United States
facility: Honor Health Shea Medical Center
state: Arizona
city: Baldwin Park
country: United States
facility: Kaiser Permanente
state: California
city: Irvine
country: United States
facility: University of California - Irvine
state: California
city: Fort Pierce
country: United States
facility: Lawnwood Regional Medical Center
state: Florida
city: Lakeland
country: United States
facility: Lakeland Regional Health
state: Florida
city: Miami
country: United States
facility: Miller School of Medicine / University of Miami Medical Center
state: Florida
city: Miami
country: United States
facility: Baptist Hospital of Miami
state: Florida
city: Tampa
country: United States
facility: Baycare St. Joseph Hospital
state: Florida
city: Brunswick
country: United States
facility: Southeast Georgia Health system
state: Georgia
city: Wailuku
country: United States
facility: Maui Health Systems
state: Hawaii
city: Carroll
country: United States
facility: St. Anthony Regional Hospital
state: Iowa
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Covington
country: United States
facility: St. Tammany Parish Hospital
state: Louisiana
city: Lafayette
country: United States
facility: Our Ladies of Lourdes Regional Hospital
state: Louisiana
city: Saint Joseph
country: United States
facility: St. Joseph Heritage Healthcare
state: Missouri
city: North Platte
country: United States
facility: Great Plains Health
state: Nebraska
city: Greenwood
country: United States
facility: Self Regional Healthcare
state: South Carolina
city: Abilene
country: United States
facility: Hendrick Medical Center
state: Texas
city: Beaumont
country: United States
facility: Baptist Hospitals of Southeast Texas
state: Texas
city: Denton
country: United States
facility: Medical City Denton
state: Texas
city: Edinburg
country: United States
facility: HR Health Institute for Research & Development
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Houston
country: United States
facility: Memorial Hermann Hospital Houston
state: Texas
city: McKinney
country: United States
facility: Medical City McKinney
state: Texas
Study officials:
affiliation: NRx Pharmaceuticals, Inc.
name: Jonathan C Javitt, MD, MPH
role: STUDY_CHAIR
References: