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Inhaled Aviptadil for the Treatment of Moderate and Severe COVID-19 (AVICOVID-2)

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: NCT04360096
Recruitment Status : Not yet recruiting
First Posted : April 24, 2020
Last Update Posted : June 29, 2020
Sponsor:
Information provided by (Responsible Party):
NeuroRx, Inc.

Brief Summary:

Brief Summary:

SARS-CoV-2 virus infection is known to cause Lung Injury that begins as dyspnea and exercise intolerance, but may rapidly progress to Critical COVID-19 with Respiratory Failure and the need for noninvasive or mechanical ventilation. Mortality rates as high as 80% have been reported among those who require mechanical ventilation, despite best available intensive care.

Patients with moderate and severe COVID-19 by FDA definition who have not developed respiratory failure be treated with nebulized RLF-100 (aviptadil, a synthetic version of Vasoactive Intestinal Polypeptide (VIP)) 100 μg 3x daily plus Standard of Care vs. placebo + Standard of Care using an FDA 501(k) cleared mesh nebulizer.

The primary outcome will be progression to in severity of COVID-19 (i.e. moderate progressing to to severe or critical OR severe progressing to critical) over 28 days. Secondary outcomes will include blood oxygenation as measured by pulse oximetry, dyspnea, exercise tolerance, and levels of TNFα IL-6 and other cytokines.


Condition or disease Intervention/treatment Phase
SARS-CoV 2 COVID ARDS ALI Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS) Dyspnea Drug: RLF-100 (aviptadil) Drug: Placebo Device: Nebulized administration of RLF-100 or Placebo Phase 2 Phase 3

Detailed Description:

Detailed Description:

Attack of the Alveolar Type II (ATII) cell via its ACE2 surface receptor by the SARS-CoV-2 virus leads to respiratory failure, morbidity, and frequently mortality in COVID-19. There is no approved treatment that specifically targets the pulmonary injury. Vasoactive Intestinal Peptide (VIP) is known to target the VPAC1 receptor of the ATII cell and to protect that cell against all manner of injuries, including smoke inhalation, exposure to stomach acid, and exposure to infectious agents. VIP prevents apoptosis, blocks cytokines, lowers TNFα levels, reverses CD4/CD8 ratio, and reduces cough and dyspnea in nonclinical and clinical studies. Aviptadil, a synthetic form of Vasoactive Intestinal Polypeptide (VIP) has been awarded FDA Orphan Drug Designation for the treatment of ARDS and Pulmonary Hypertension and EMEA Orphan Drug Designation for the treatment of ARDS and Sarcoid. RLF-100 (Aviptadil) has been granted FDA Fast Track Designation for the treatment of ARDS/Acute Lung Injury in COVID-19.

The objective of this study is to identify patients with moderate and severe COVID-19 who have not yet developed respiratory failure and to treat them with inhaled Vasoactive Intestinal Polypeptide (VIP) in the hope of preventing progression to Critical COVID-19 with Respiratory Failure.

Nonclinical studies demonstrate that VIP is 70% concentrated in the lung, where it binds primarily to ATII cells. VIP prevents NMDA-induced caspase-3 activation in the lung, inhibits IL6 and TNFα production, protects against HCl-induced pulmonary edema, 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.

Both intravenous and inhalation preclinical toxicology and safety pharmacology have been performed in four species, with a six month trial of inhaled RLF-100 in primates.

Aviptadil is approved for human use in Europe and has a demonstrated 20 year history of safety in numerous trials for Sarcoid, Pulmonary Fibrosis, Bronchospasm, Erectile Dysfunction, 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 GCP phase 2 trials of RLF-100 have been conducted under European regulatory authority. Non GCP 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 patients with moderate and severe COVID-19 by FDA definition who have not developed respiratory failure be treated with nebulized RLF-100 100 μg 3x daily plus Standard of Care vs. placebo + Standard of Care using an FDA 501(k) cleared mesh nebulizer.

The primary outcome will be progression to in severity of COVID-19 (i.e. moderate progressing to to severe or critical OR severe progressing to critical) over 28 days. Secondary outcomes will include blood oxygenation as measured by pulse oximetry, dyspnea, exercise tolerance, and levels of TNFα IL-6 and other cytokines.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 288 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Multicenter Randomized Placebo-controlled Trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Only the study pharmacist will be aware of treatment assignment
Primary Purpose: Treatment
Official Title: Inhaled Aviptadil for the Treatment of Moderate and Severe COVID-19
Estimated Study Start Date : July 1, 2020
Estimated Primary Completion Date : October 1, 2020
Estimated Study Completion Date : November 30, 2020


Arm Intervention/treatment
Experimental: Moderate COVID-19 RLF-100
Patients with Moderate COVID-19 to be treated with inhaled RLF-100 (aviptadil) by mesh nebulizer 100μg 3x daily
Drug: RLF-100 (aviptadil)
Inhaled RLF-100 (aviptadil) 100μg 3x daily by mesh nebulizer

Device: Nebulized administration of RLF-100 or Placebo
Use of 510(k) cleared mesh nebulizer to deliver investigational product

Experimental: Moderate COVID-19 Placebo
Patients with Moderate COVID-19 to be treated with inhaled placebo 3x daily
Drug: Placebo
Normal Saline Inhalation

Device: Nebulized administration of RLF-100 or Placebo
Use of 510(k) cleared mesh nebulizer to deliver investigational product

Experimental: Severe COVID-19 RLF-100
Patients with Severe COVID-19 to be treated with inhaled RLF-100 (aviptadil) by mesh nebulizer 100μg 3x daily
Drug: RLF-100 (aviptadil)
Inhaled RLF-100 (aviptadil) 100μg 3x daily by mesh nebulizer

Device: Nebulized administration of RLF-100 or Placebo
Use of 510(k) cleared mesh nebulizer to deliver investigational product

Experimental: Severe COVID-19 Placebo
Patients with Severe COVID-19 to be treated with inhaled placebo 3x daily
Drug: Placebo
Normal Saline Inhalation

Device: Nebulized administration of RLF-100 or Placebo
Use of 510(k) cleared mesh nebulizer to deliver investigational product




Primary Outcome Measures :
  1. Progression to ARDS [ Time Frame: 28 days ]
    Progression to ARDS is defined as the need for mechanical ventilation


Secondary Outcome Measures :
  1. Blood oxygenation [ Time Frame: 28 days ]
    Blood PO2 as measured by pulse oximetry

  2. RDP Dsypnea Scale [ Time Frame: 28 days ]

    0 = no shortness of breath at all 0.5 = very, very slight shortness of breath

    1. = very mild shortness of breath
    2. = mild shortness of breath
    3. = moderate shortness of breath or breathing difficulty
    4. = somewhat severe shortness of breath
    5. = strong or hard breathing

    7 = severe shortness of breath or very hard breathing 8 9 = extremely severe shortness of breath 10 = shortness of breath so severe you need to stop the exercise or activity


  3. Distance walked in six minutes [ Time Frame: 28 days ]
    Distance walked in six minutes



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:   12 Years to 85 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Moderate or Severe COVID-19 by FDA definition with no evidence of Respiratory Failure
  2. Capable of using mesh nebulizer to administer medication with assistance if needed

Exclusion Criteria:

  1. Evidence of Respiratory Failure
  2. Use or impending use of ventilation or high flow nasal oxygen 20L or greater

4) Age <12 years; 5) Diastolic pressure < 65 mm Hg; 6) Irreversible underlying condition with projected fatal course; 7) Immunosuppressive treatment for transplant or other reasons; 8) Cancer, renal failure, congestive heart failure, neurological disorder 9) Recent myocardial infarction with Troponin >0.5


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): NCT04360096


Contacts
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Contact: Robert E Besthof, MIM +48425461134 rbesthof@neurorxpharma.com

Sponsors and Collaborators
NeuroRx, Inc.
Investigators
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Study Chair: Jonathan C Javitt, MD, MPH NeuroRx
Additional Information:
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Responsible Party: NeuroRx, Inc.
ClinicalTrials.gov Identifier: NCT04360096    
Other Study ID Numbers: RLF-100_002
First Posted: April 24, 2020    Key Record Dates
Last Update Posted: June 29, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Keywords provided by NeuroRx, Inc.:
Corona Virus
VIP
Aviptadil
Vasoactive Intestinal Polypeptide
Additional relevant MeSH terms:
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Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Acute Lung Injury
Dyspnea
Lung Injury
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Signs and Symptoms, Respiratory
Signs and Symptoms
Thoracic Injuries
Wounds and Injuries