Clinical trial NCT04360096: Inhaled ZYESAMI™ (Aviptadil Acetate) for the Treatment of Severe COVID-19
Official title: Inhaled ZYESAMI™ for the Treatment of Severe COVID-19
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: SARS-CoV 2
COVID
ARDS
ALI
Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS)
Dyspnea
Keywords: Corona Virus
VIP
Aviptadil
Vasoactive Intestinal Polypeptide
Lead sponsor: APR Applied Pharma Research s.a.
Sponsor class: OTHER
First posted: 2020-04-24
Enrollment: 144
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter Randomized Placebo-controlled Trial
Primary purpose: TREATMENT

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 severe COVID-19 by FDA definition who have not developed respiratory failure be treated with nebulized ZYESAMI™ (aviptadil acetate, 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 in severity of COVID-19 (i.e. 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.

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 acetate, 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. ZYESAMI™ (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 severe COVID-19 who have not yet developed respiratory failure and to treat them with inhaled ZYESAMI™ 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 Aviptadil in primates.

Aviptadil is approved for human use in the treatment of erectile dysfunction in Scandinavia and several European countries in co-formulation with phentolamine and has a demonstrated phase 2 safety in trials for Sarcoid, Pulmonary Fibrosis, and Bronchospasm. No adverse safety signals were seen in a phase I trial IV Aviptadil 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.

A 60-day phase 2b/3 trial of IV Aviptadil (NCT 04311697) has recently completed enrollment and 28-day top-line safety data have been reported. No unanticipated serious adverse events were reported. The only adverse event that was statistically more frequent in Aviptadil-treated participants than among placebo-treated participants was mild to moderate diarrhea, which has not been reported as a frequent side-effect of inhaled Aviptadil (30% vs 1.5%; p\< .001). Systemic hypotension was seen in both Aviptadil-treated and placebo-treated participants (25% vs 18.5%; P=NS).

Five GCP phase 2 trials of Aviptadil were 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 with severe COVID-19 by FDA definition who have not developed respiratory failure will be treated with nebulized ZYESAMI™ 100 μg in 1 cc normal saline 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. 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.

Eligibility criteria: Inclusion criteria:

1. Severe COVID-19 , as defined by clinical signs indicative of severe systemic illness with COVID-19, being given oxygenation and meeting

   ONE of the following:

   Respiratory rate ≥ 30 per minute Heart rate ≥ 125 per minute SpO2 ≤ 93% on room air at sea level PaO2/FiO2 \< 300 mmHg or SpO2/FiO2 \< 315 mmHg
2. Positive test by standard RT-PCR assay or equivalent within last 7 days
3. Physician determination that patient is on SOC therapy, and will receive standard of care if patient progresses to Critical COVID-19, patient must be full CODE

Exclusion criteria:

1. Evidence of Critical COVID-19
2. Inability to utilize nebulized drugs, or history of bronchospasm with inhaled medications
3. Age \<12 years;
4. Mean arterial pressure \< 65 mm Hg after initial hospital stabilization,
5. Non-COVID-19 irreversible underlying condition with projected fatal course within 6 months or with high risk of mortality;
6. Immunosuppressive treatment for transplant or other diseases associated with high mortality;
7. Stage IV cancer or cancer on active treatment with chemotherapy immunotherapy or checkpoint inhibitors; acute renal failure or chronic renal insufficiency with GFR less than 30; CHF New York Heart Association class III or IV, new neurologic disorder in the last 3 months or chronic neurologic disorder or other that would impact on assessing the resolution of severe COVID-19 respiratory failure
8. Myocardial Infarction in previous six months or troponin \>0.5
9. Recent history of venous thrombotic events (PE / DVT) within the last 3 months.
10. New diagnosis of atrial fibrillation within the last 3 months. Acceptable if greater than 3 months and well controlled in the opinion of the investigator
11. Watery diarrhea requiring replacement of 1 liter or more of iv fluids and electrolytes
12. Pregnancy

Primary outcomes:
measure: Progression to Respiratory Failure
timeFrame: 28 days
Secondary outcomes:
measure: Blood oxygenation
timeFrame: 28 days
measure: RPD Dyspnea Scale
timeFrame: 28 days
measure: Distance walked in six minutes
timeFrame: 28 days
Other outcomes:
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: University of Miami Leonard M. Miller School of Medicine (UMMSM)
state: Florida
city: Orlando
country: United States
facility: Advent Health Research Institute
state: Florida
city: Winfield
country: United States
facility: Northwestern Medical Group
state: Illinois
city: Louisville
country: United States
facility: University of Louisville Hospital
state: Kentucky
city: North Platte
country: United States
facility: Great Plains Health
state: Nebraska
city: Las Vegas
country: United States
facility: University Medical Center
state: Nevada
city: Teaneck
country: United States
facility: Holy Name Medical Center
state: New Jersey
city: Kettering
country: United States
facility: Kettering Health Network
state: Ohio
city: Doylestown
country: United States
facility: Doylestown Hospital
state: Pennsylvania
city: Greenwood
country: United States
facility: Self Regional Healthcare
state: South Carolina
city: San Antonio
country: United States
facility: University of Texas San Antonio Medical Arts and Research Center
state: Texas
Study officials:
affiliation: NeuroRx
name: Jonathan C Javitt, MD, MPH
role: STUDY_CHAIR
References: