<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04453839</url>
  </required_header>
  <id_info>
    <org_study_id>ZYESAMI_EA-1</org_study_id>
    <nct_id>NCT04453839</nct_id>
  </id_info>
  <brief_title>ZYESAMI (Aviptadil) Intermediate Population Expanded Access Protocol (SAMICARE)</brief_title>
  <acronym>SAMICARE</acronym>
  <official_title>ZYESAMI (Aviptadil) Intermediate Population Expanded Access Protocol</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>APR Applied Pharma Research s.a.</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>APR Applied Pharma Research s.a.</source>
  <brief_summary>
    <textblock>
      Patients with Critical COVID-19 and respiratory failure who are ineligible for enrollment in&#xD;
      NCT04311697, who live more than 50 miles from an existing collaborating research center, or&#xD;
      who are already hospitalized and cannot safely be transferred to a collaborating research&#xD;
      facility may be considered for expanded access by the sponsor.&#xD;
&#xD;
      Treating physicians must complete FDA Form 3396 and receive a letter of authorization from&#xD;
      NeuroRx, along with local IRB authorization.&#xD;
&#xD;
      Please refer to FDA guidance for Individual Patient Expanded Access&#xD;
      https://www.fda.gov/media/91160/download&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      5. INTRODUCTION&#xD;
&#xD;
      5.1 Executive Summary ZYESAMI (aviptadil) is a synthetic form of Vasoactive Intestinal&#xD;
      Polypeptide (VIP), a ubiquitous, naturally synthesized human peptide with extensively&#xD;
      documented anti-inflammatory, anti-cytokine cascade properties. It has been granted FDA Fast&#xD;
      Track Designation for treatment of Critical COVID-19 with Respiratory Failure. A phase 2/3&#xD;
      trial is underway that has passed its first evaluation at 30 patients for safety and&#xD;
      futility. This expanded access protocol is designed to offer access to investigational use of&#xD;
      RLF-100 to patients who do not qualify for inclusion in Protocol RLF-100-001 (NCT04311697)&#xD;
      either on the basis of specific medical exclusions or because there is no accessible study&#xD;
      site available to the prospective participant.&#xD;
&#xD;
      5.2 Definition of Critical COVID-19&#xD;
&#xD;
      In May 2020, FDA defined Critical COVID-19 to be used in clinical trials and disease staging&#xD;
      as follows:&#xD;
&#xD;
      Critical COVID-19&#xD;
&#xD;
        -  Positive testing by standard RT-PCR assay or an equivalent test&#xD;
&#xD;
        -  Evidence of Respiratory Failure based on FDA definition of: need for Endotracheal&#xD;
           intubation and mechanical ventilation, oxygen delivered by high-flow nasal cannula&#xD;
           (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates &gt; 20&#xD;
           L/min with fraction of delivered oxygen ≥ 0.5), noninvasive positive pressure&#xD;
           ventilation, ECMO, or clinical diagnosis of respiratory failure (i.e., clinical need for&#xD;
           one of the preceding therapies, but preceding therapies not able to be administered in&#xD;
           setting of resource limitation)&#xD;
&#xD;
      Acute Lung Injury in COVID-19 is characterized by progressive failure of corporeal&#xD;
      oxygenation, attributed on large part by SARS-CoV-2 infection of Alveolar Type II cells&#xD;
      (Mason 2020). Extensive nonclinical studies document that 70% of VIP in the body binds to&#xD;
      receptors on the Alveolar Type II cell, where VIP is known to block cytokine production and&#xD;
      upregulate production of surfactant.&#xD;
&#xD;
      Severity of COVID is associated with and graded by a progressively worsened state of&#xD;
      oxygenation. This is seen in the PaO2/FIO2 ratio, which reflects the status of oxygenation&#xD;
      for patients on high pressure oxygen and mechanical ventilation. In patients breathing room&#xD;
      air, disease severity is assessed by SpO2. Many patients with Critical COVID meet the&#xD;
      clinical definitions of Acute Respiratory Distress Syndrome (ARDS). However, there is&#xD;
      increasing recognition that respiratory distress in COVID-19 has different characteristics&#xD;
      than ARDS in the setting of bacterial sepsis and other common presentations of ARDS.&#xD;
&#xD;
      The pathologic hallmark of COVID-19 lung injury is diffuse alveolar damage, vascular&#xD;
      endothelium damage, and damage to the surfactant-producing type II cells which results in&#xD;
      loss of the integrity of the alveolar-capillary barrier, transudation of protein-rich fluid&#xD;
      across the barrier, pulmonary edema, and hypoxemia from intrapulmonary shunting. Typically,&#xD;
      patients who have progressed to Critical COVID-19 require care in an intensive care unit&#xD;
      (ICU). The mortality rate is approximately 50%. Deaths usually result from multisystem organ&#xD;
      failure rather than lung failure alone.&#xD;
&#xD;
      5.3 ZYESAMI Experimental Therapy in COVID-19&#xD;
&#xD;
      Under this protocol, patients with Critical COVID-19 will be treated with ZYESAMI (Aviptadil)&#xD;
      with the aim to support pulmonary alveolar function, combat the cytokine-induced&#xD;
      inflammation, improve blood oxygenation, and reduce mortality.&#xD;
&#xD;
      5.4 Clinical Rationale Given by intravenous infusion in appropriate concentrations, ZYESAMI&#xD;
      has been shown in clinical trials to have a manageable safety profile with no observed SAEs&#xD;
      to date that would rise to the level of a black box warning.&#xD;
&#xD;
      6. OBJECTIVES&#xD;
&#xD;
      6.1 Primary Objective The primary objective of this study is to measure the effectiveness and&#xD;
      safety of ZYESAMI + maximal standard of care (SOC) in treating Critical COVID-19 with&#xD;
      Respiratory Failure.&#xD;
&#xD;
      6.2 Secondary Objective The key secondary objective is to test the hypothesis that ZYESAMI&#xD;
      improves blood oxygenation as measured by SaO2.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>No longer available</overall_status>
  <study_type>Expanded Access</study_type>
  <has_expanded_access>No</has_expanded_access>
  <expanded_access_info>
    <expanded_access_type_intermediate>Yes</expanded_access_type_intermediate>
  </expanded_access_info>
  <condition>Critical COVID-19 With Respiratory Failure</condition>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ZYESAMI (aviptadil acetate)</intervention_name>
    <description>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</description>
    <other_name>Vasoactive Intestinal Peptide</other_name>
    <other_name>VIP</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Critical COVID-19 with Respiratory Failure&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who are eligible for enrollment in RLF-100_001 are excluded from this&#xD;
             protocol and live within 50 miles of a study site for NCT04311697 cannot be enrolled&#xD;
             unless already admitted to an ICU and ineligible for transfer&#xD;
&#xD;
          -  Mean Arterial Pressure &lt; 65 mm Hg with use of pressor per ICU protocol&#xD;
&#xD;
          -  Irreversible condition (other than COVID-19) with projected fatal course&#xD;
&#xD;
          -  ECMO&#xD;
&#xD;
          -  Chemotherapy-induced neutropenia (granulocyte count &lt;1000/mm3);&#xD;
&#xD;
          -  Cardiogenic shock; congestive heart failure - NYHA Class 3 or 4;&#xD;
&#xD;
          -  Liquid Diarrhea more than 3x/day; defined as more than 3 non-bloody watery stools&#xD;
             within a 24-hour period, requiring additional fluid and electrolyte supplementation&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>12 Years</minimum_age>
    <maximum_age>100 Years</maximum_age>
  </eligibility>
  <overall_official>
    <last_name>Jonathan C Javitt, MD, MPH</last_name>
    <role>Study Chair</role>
    <affiliation>NRx Pharmaceuticals, Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Dignity Health-Mercy Gilbert Medical Center</name>
      <address>
        <city>Gilbert</city>
        <state>Arizona</state>
        <zip>85297</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Honor Health Shea Medical Center</name>
      <address>
        <city>Scottsdale</city>
        <state>Arizona</state>
        <zip>85260</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kaiser Permanente</name>
      <address>
        <city>Baldwin Park</city>
        <state>California</state>
        <zip>91706</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California - Irvine</name>
      <address>
        <city>Irvine</city>
        <state>California</state>
        <zip>92697</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lawnwood Regional Medical Center</name>
      <address>
        <city>Fort Pierce</city>
        <state>Florida</state>
        <zip>34950</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lakeland Regional Health</name>
      <address>
        <city>Lakeland</city>
        <state>Florida</state>
        <zip>33805</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Miller School of Medicine / University of Miami Medical Center</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baptist Hospital of Miami</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33176</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baycare St. Joseph Hospital</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33607</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Southeast Georgia Health system</name>
      <address>
        <city>Brunswick</city>
        <state>Georgia</state>
        <zip>31520</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Maui Health Systems</name>
      <address>
        <city>Wailuku</city>
        <state>Hawaii</state>
        <zip>96793</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Anthony Regional Hospital</name>
      <address>
        <city>Carroll</city>
        <state>Iowa</state>
        <zip>51401</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Louisville</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Tammany Parish Hospital</name>
      <address>
        <city>Covington</city>
        <state>Louisiana</state>
        <zip>70433</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Our Ladies of Lourdes Regional Hospital</name>
      <address>
        <city>Lafayette</city>
        <state>Louisiana</state>
        <zip>70508</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Joseph Heritage Healthcare</name>
      <address>
        <city>Saint Joseph</city>
        <state>Missouri</state>
        <zip>64506</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Great Plains Health</name>
      <address>
        <city>North Platte</city>
        <state>Nebraska</state>
        <zip>69101</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Self Regional Healthcare</name>
      <address>
        <city>Greenwood</city>
        <state>South Carolina</state>
        <zip>29646</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hendrick Medical Center</name>
      <address>
        <city>Abilene</city>
        <state>Texas</state>
        <zip>79601</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baptist Hospitals of Southeast Texas</name>
      <address>
        <city>Beaumont</city>
        <state>Texas</state>
        <zip>77701-4689</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical City Denton</name>
      <address>
        <city>Denton</city>
        <state>Texas</state>
        <zip>76210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HR Health Institute for Research &amp; Development</name>
      <address>
        <city>Edinburg</city>
        <state>Texas</state>
        <zip>78539</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Houston Methodist Hospital</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Hermann Hospital Houston</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical City McKinney</name>
      <address>
        <city>McKinney</city>
        <state>Texas</state>
        <zip>75609</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://europepmc.org/article/ppr/ppr342295</url>
    <description>Intravenous Aviptadil Is Associated with Increased Recovery and Survival in Patients with COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial</description>
  </link>
  <link>
    <url>https://journals.lww.com/ccejournal/Fulltext/2022/01000/Brief_Report__Rapid_Clinical_Recovery_From.1.aspx</url>
    <description>Brief Report: Rapid Clinical Recovery From Critical Coronavirus Disease 2019 With Respiratory Failure in a Pregnant Patient Treated With IV Vasoactive Intestinal Peptide</description>
  </link>
  <verification_date>January 2022</verification_date>
  <study_first_submitted>June 27, 2020</study_first_submitted>
  <study_first_submitted_qc>June 30, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 1, 2020</study_first_posted>
  <last_update_submitted>February 2, 2023</last_update_submitted>
  <last_update_submitted_qc>February 2, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 3, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Respiratory Insufficiency</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vasoactive Intestinal Peptide</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>August 15, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/39/NCT04453839/Prot_001.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>October 19, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/39/NCT04453839/ICF_002.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04453839
org study id: ZYESAMI_EA-1
nct id: NCT04453839
lead sponsor: 
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.
expanded access type intermediate: Yes
intervention type: Drug
intervention name: ZYESAMI (aviptadil acetate)
description: 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: Vasoactive Intestinal Peptide
other name: VIP
criteria: 
gender: All
minimum age: 12 Years
maximum age: 100 Years
last name: Jonathan C Javitt, MD, MPH
role: Study Chair
affiliation: NRx Pharmaceuticals, Inc.
facility: 
facility: 
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facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
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facility: 
facility: 
facility: 
facility: 
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facility: 
country: United States
url: https://europepmc.org/article/ppr/ppr342295
description: Intravenous Aviptadil Is Associated with Increased Recovery and Survival in Patients with COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial
url: https://journals.lww.com/ccejournal/Fulltext/2022/01000/Brief_Report__Rapid_Clinical_Recovery_From.1.aspx
description: Brief Report: Rapid Clinical Recovery From Critical Coronavirus Disease 2019 With Respiratory Failure in a Pregnant Patient Treated With IV Vasoactive Intestinal Peptide
responsible party type: Sponsor
mesh term: Respiratory Insufficiency
mesh term: Vasoactive Intestinal Peptide
provided document: 
provided document: 