Clinical trial NCT04311697: Intravenous Aviptadil for Critical COVID-19 With Respiratory Failure
Official title: ZYESAMI (Aviptadil) for the Treatment of Critical COVID-19 With Respiratory Failure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Critical COVID-19 With Respiratory Failure
Acute Respiratory Distress Syndrome (ARDS)
Corona Virus Infection
Acute Lung Injury
Keywords: COVID-19
ARDS
Aviptadil
Acute Respiratory Distress Syndrome
Respiratory Failure
Lead sponsor: APR Applied Pharma Research s.a.
Sponsor class: OTHER
First posted: 2020-03-17
Enrollment: 203
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter trial, initially conducted at a single center with a safety/futility assessment following enrollment of 30 patients, expanded to 196 total patients at 12 study sites
Primary purpose: TREATMENT

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 ZYESAMI (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.

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.

Eligibility 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

Primary outcomes:
measure: Resolution of Respiratory Failure (Alive and Free of Respiratory Failure)
timeFrame: Day 28
Secondary outcomes:
measure: Number of Participants Alive at Day 60
timeFrame: Day 60
measure: Number of Participants Achieving a Score of 6-8 on NIAID Ordinal Score Through Day 60
timeFrame: Day 60
measure: Oxygenation Index as Measured by PaO2:FiO2 Ratio
timeFrame: Day 7
Other outcomes:
measure: Change in IL-6
timeFrame: Day 28
Locations:
city: Fullerton
country: United States
facility: St. Jude Medical Center
state: California
city: Irvine
country: United States
facility: University of California - Irvine
state: California
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: Louisville
country: United States
facility: University of Louisville Hospital
state: Kentucky
city: Saint Joseph
country: United States
facility: Heartland/Mosaic Health
state: Missouri
city: Abilene
country: United States
facility: Hendrick Health
state: Texas
city: Fort Worth
country: United States
facility: Texas Health Harris Methodist Hospital
state: Texas
city: Frisco
country: United States
facility: Texas Health Hospital Frisco
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
Study officials:
affiliation: NeuroRx, Inc.
name: Jonathan C Javitt, MD, MPH
role: STUDY_CHAIR
References: