Inhaled Aviptadil for the Treatment of Non-Acute Lung Injury in COVID-19 (AVINALI)

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

Study Description

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 Acute Respiratory Distress Syndrome and the need for mechanical ventilation. Mortality rates as high as 80% have been reported among those who develop ARDS, despite intensive care and mechanical ventilation.

Patients with COVID-19 induced non-Acute Lung Injury who have demonstrated reduction in blood oxygenation, dyspnea, and exercise intolerance but do not require endotracheal intubation and mechanical ventilation will be treated with Aviptadil, a synthetic version of Vasoactive Intestinal Polypeptide (VIP) plus Standard of Care vs. placebo + Standard of Care. Patients will be randomized to intravenous Aviptadil will receive inhaled Aviptadil, 100 μg 3x daily vs. placebo 3x daily. The primary outcome will be progression to ARDS 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: Aviptadil (VIP); Drug: Placebo	Phase 2; Phase 3

Detailed Description:

Detailed Description:

Acute Respiratory Distress Syndrome (ARDS) 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.

The objective of this study is to identify patients with non-Acute Lung Injury (NALI) in COVID-19 and treat them with inhaled Vasoactive Intestinal Polypeptide (VIP) in the hope of preventing progression from NALI to Acute Lung Injury and ARDS. Aviptadil, a synthetic form of Vasoactive Intestinal Polypeptide (VIP) has been awarded FDA Orphan Drug Designation for the treatment of ARDS.

Nonclinical studies demonstrate that VIP is highly concentrated in the lung, where it prevents NMDA-induced caspase-3 activation in the lung, inhibits IL6 and TNFa 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.

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 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 COVID-19 infection with NALI but no evidence of ARDS will be randomly allocated to Aviptadil administered by inhalation in addition to Standard of Care vs. Placebo plus Standard of Care. Primary endpoints will be progression to ARDS over 28 days and improvement in blood oxygenation. Secondary outcomes will include blood oxygenation as measured by pulse oximetry, dyspnea, exercise tolerance, and levels of TNFα IL-6 and other cytokines.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 144 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 Non-Acute Lung Injury in COVID-19
• Estimated Study Start Date: June 1, 2020
• Estimated Primary Completion Date: August 1, 2020
• Estimated Study Completion Date: October 1, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Inhaled Aviptadil (VIP)+Standard of Care; Patients to be treated with inhaled Aviptadil 100μg 3x daily	Drug: Aviptadil (VIP); Inhaled Aviptadil 100μg 3x daily
Experimental: Placebo+Standard of Care; Patients to be treated with inhaled placebo 3x daily	Drug: Placebo; Normal Saline Inhalation

Outcome Measures

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. COVID-19 with evidence of Lung Injury as demonstrated by PO2 of <90 measured by pulse oximetry.
2. Physician determination that patient is on maximal SOC therapy-

Exclusion Criteria:

1. Evidence of ARDS or need for mechanical ventilation
2. Impending ICU admission
3. Pregnancy;
4. Age <18 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
10. Diarrhea

Contacts and Locations

Contacts

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

Sponsors and Collaborators

NeuroRx, Inc.

Investigators

• Study Chair: Jonathan C Javitt, MD, MPH; NeuroRx

More Information

• Responsible Party: NeuroRx, Inc.
• ClinicalTrials.gov Identifier: NCT04360096
• Other Study ID Numbers: RLF-100_002
• First Posted: April 24, 2020
• Last Update Posted: April 24, 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)

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by NeuroRx, Inc.:

Corona Virus; VIP; Aviptadil; Vasoactive Intestinal Polypeptide

Additional relevant MeSH terms:

Respiratory Distress Syndrome, Newborn; Respiratory Distress Syndrome, Adult; Acute Lung Injury; Dyspnea; Lung Injury; Wounds and Injuries; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Infant, Premature, Diseases; Infant, Newborn, Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Thoracic Injuries