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Intravenous Aviptadil for Critical COVID-19 With Respiratory Failure (COVID-AIV)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04311697
Recruitment Status : Recruiting
First Posted : March 17, 2020
Last Update Posted : June 4, 2020
Sponsor:
Collaborators:
Relief Therapeutics Holding SA
Target Health Inc.
Lavin Consulting, LLC
Information provided by (Responsible Party):
NeuroRx, Inc.

Brief Summary:
Novel Corona Virus (SARS-CoV-2) is known to cause Respiratory Failure, which is the hallmark of Acute COVID-19, as defined by the new NIH/FDA classification. Approximately 50% of those who develop Critical COVID-19 die, despite intensive care and mechanical ventilation. Patients with Critical COVID-19 and respiratory failure, currently treated with high flow nasal oxygen, non-invasive ventilation or mechanical ventilation will be treated with Aviptadil, a synthetic form of Human Vasoactive Intestinal Polypeptide (VIP) plus maximal intensive care vs. placebo + maximal intensive care. Patients will be randomized to intravenous Aviptadil will receive escalating doses from 50 -150 pmol/kg/hr over 12 hours.

Condition or disease Intervention/treatment Phase
Critical COVID-19 With Respiratory Failure Acute Respiratory Distress Syndrome (ARDS) Corona Virus Infection Acute Lung Injury Drug: Aviptadil by intravenous infusion + standard of care Drug: Normal Saline Infusion + standard of care Phase 2

Detailed Description:

Acute Lung Injury, which triggers Critical COVID-19 is a known lethal complication of Corona Virus (SARS-CoV-2) infection. Conventional medical therapy, including intensive care and respiratory support is associated with an 80% mortality. Aviptadil, a synthetic form of Human Vasoactive Intestinal Polypeptide (VIP) has been awarded FDA Orphan Drug Designation for the treatment of ARDS and admitted to the FDA CoronaVirus Technology Accelerator Program.

VIP binds to VPAC1 receptors on the pulmonary Alveolar Type II (ATII) cell. ATII cells comprise only 5% of lung epithelial cells but are critical for oxygen transfer, surfactant production, and maintenance of Alveolar Type 1 cells. 70% of VIP binds to this receptor. The Type II cell is also the cell selectively attacked by the SARS-CoV-2 virus via the ACE2 surface receptor.

Nonclinical studies demonstrate that VIP is highly concentrated in the lung and specifically bound to the ATII cell, where it prevents NMDA-induced caspase-3 activation in the lung, inhibits IL6 and TNFa production, protects against HCl-induced pulmonary edema, and upregulates surfactant production, These and other effects have been observed in numerous animal model systems of lung injury in mice, rats, guinea pigs, sheep, swine, and dogs. In these models, Aviptadil restores barrier function at the endothelial/alveolar interface and thereby protects the lung and other organs from failure.

Aviptadil ihas a demonstrated 20 year history of safety in phase 2 trials for Sarcoid, Pulmonary Fibrosis, Bronchospasm, and a phase I trial in ARDS. In that phase I trial, 8 patients with severe ARDS on mechanical ventilation were treated with ascending doses of VIP. Seven of the 8 patients were successfully extubated and were alive at the five day timepoint. Six left the hospital and one died of an unrelated cardiac event.

Five phase 2 trials of aviptadil have been conducted under European regulatory authority. Numerous healthy volunteer studies have shown that i.v. infusion of Aviptadil is well tolerated with few adverse effects including alterations in blood pressure, heart rate, or ECG. In addition to published studies of human use, Aviptadil has been used on a compounded basis in certain ICUs for many years in the belief that it preserves life and restores function in pulmonary hypertension, ARDS, and Acute Lung Injury (ALI).

In this study, patients who are hospitalized for Critical COVID-19 infection with respiratory failure will be randomly allocated to Aviptadil administered by intravenous infusion in addition to maximal intensive care vs. maximal intensive care alone. Primary endpoints will be improvement in blood oxygenation and mortality.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 144 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Multicenter trial, initially conducted at a single center with a safety/futility assessment following enrollment of 30 patients
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Randomized, placebo-controlled trial with identical drug and placebo infusion bags
Primary Purpose: Treatment
Official Title: Intravenous Aviptadil for Critical COVID-19 With Respiratory Failure
Actual Study Start Date : May 15, 2020
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : September 2020


Arm Intervention/treatment
Experimental: Aviptadil IV in escalating doses + standard of care
Patients will be administered Aviptadil IV in escalating doses of 50 pmol, 100 pmol, 150 pmol/kg/hr
Drug: Aviptadil by intravenous infusion + standard of care
Aviptadil by intravenous infusion + standard of care (SOC). SOC is defined not to include extracorporeal mechanical oxygenation. Those requiring ECMO will be withdrawn from the study as treatment failures.

Experimental: Placebo + standard of care
Patients will first be treated with placebo infusion + maximal intensive care
Drug: Normal Saline Infusion + standard of care
Saline by intravenous infusion + standard of care (SOC). SOC is defined not to include extracorporeal mechanical oxygenation. Those requiring ECMO will be withdrawn from the study as treatment failures.




Primary Outcome Measures :
  1. Mortality [ Time Frame: 5 Days with followup through 30 days ]
    Mortality

  2. PaO2:FiO2 ratio [ Time Frame: 5 Days with followup through the end of telemetry monitoring ]
    Index of Respiratory Distress


Secondary Outcome Measures :
  1. TNF alpha [ Time Frame: 5 Days ]
    TNF alpha levels as measured in hospital laboratory

  2. Multi-system organ failure free days [ Time Frame: 5 days with followup through 30 days ]
    Multi-system organ failure free days



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Critical COVID-19 with respiratory failure
  • Physician determination that patient is on maximal conventional medical therapy

Exclusion Criteria:

  1. Pregnancy (pregnant women may apply for open label treatment under compassionate care IND
  2. Age <18 years
  3. Mechanical ventilation for more than 7 days in primary cohort. Mechanical ventilation>21 days in the exploratory cohort
  4. Mean Arterial Pressure < 65 mm Hg with use of pressor per ICU protocol
  5. Irreversible condition (other than COVID-19) with projected fatal course
  6. ECMO
  7. Current or recent (within 30 d) enrollment in another investigational trial of anti-IL6 drug;
  8. Active diagnosis of Acquired immune deficiency syndrome;
  9. Transplant patients currently immunosuppressed;
  10. Chemotherapy-induced neutropenia (granulocyte count <1000/mm3);
  11. Cardiogenic shock; congestive heart failure - NYHA Class 3 or 4;
  12. Recent myocardial infarction - within last 6 months and troponin > 0.5
  13. Anuria (urine output < 50 ml/d) or other signs of multi-organ failure
  14. Severe liver disease with portal hypertension;
  15. Recent stroke or head trauma within last 12 months
  16. Increased intracranial pressure, or other serious neurologic disorder;
  17. 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

Information from the National Library of Medicine

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): NCT04311697


Contacts
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Contact: Robert E Besthof, MIM +14842546134 ext 701 rbesthof@neurorxpharma.com

Locations
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United States, California
University of California - Irvine Recruiting
Irvine, California, United States, 92697
Contact: Richard Lee, MD       richaral@hs.uci.edu   
Principal Investigator: Richard Lee, MD         
United States, Florida
Miller School of Medicine / University of Miami Medical Center Recruiting
Miami, Florida, United States, 33136
Contact: Dushyantha Jayaweera, MD       DJayawee@med.miami.edu   
Principal Investigator: Dushyanatha Jayaweera, MD         
Sub-Investigator: Daniel H Kett, MD         
Sub-Investigator: Daniel D Yeh, MD         
United States, New York
Robert I Grossman School of Medicine / NYU Langone Medical Center Not yet recruiting
New York, New York, United States, 10016
Principal Investigator: Daniel H Sterman, MD         
United States, Pennsylvania
Thomas Jefferson University Hospital Not yet recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Ross Summer, MD         
Israel
Rambam Health Care Campus Not yet recruiting
Haifa, Israel, 3109601
Contact: Yaron Bar-Lavie, MD, FCCP    04-777-2601    y_barlavie@rambam.health.gov.il   
Principal Investigator: Yaron Bar-Lavie, MD, FCCP         
Sponsors and Collaborators
NeuroRx, Inc.
Relief Therapeutics Holding SA
Target Health Inc.
Lavin Consulting, LLC
Investigators
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Study Chair: Jonathan C Javitt, MD, MPH NeuroRx, Inc.
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Responsible Party: NeuroRx, Inc.
ClinicalTrials.gov Identifier: NCT04311697    
Other Study ID Numbers: COVID-AIV
First Posted: March 17, 2020    Key Record Dates
Last Update Posted: June 4, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by NeuroRx, Inc.:
COVID-19
ARDS
Aviptadil
Acute Respiratory Distress Syndrome
Respiratory Failure
Additional relevant MeSH terms:
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Coronavirus Infections
Severe Acute Respiratory Syndrome
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Respiratory Insufficiency
Acute Lung Injury
Lung Injury
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Virus Diseases
Thoracic Injuries
Wounds and Injuries
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Respiratory Tract Infections