VIP in the Treatment of Critical COVID-19 Respiratory Failure in Patients with Severe Comorbidities

Abstract

Importance: There is currently no effective drug for Critical COVID-19 with Respiratory Failure, particularly in highly comorbid patients and mortality is in excess of 30%. Vasoactive Intestinal Peptide (VIP) blocks replication of the SARS-CoV-2 virus, inhibits cytokine synthesis, prevents cytopathy, and upregulates surfactant production in human pulmonary cells. Objective: To determine the safety and efficacy of intravenous aviptadil (synthetic VIP) for improving survival and recovery from respiratory failure in patients with Critical COVID-19 and severe comorbidity who are ineligible for phase 3 trials of aviptadil.Design: Prospective, open-label, administrativelycontrolled trial, measuring objective endpoints only. Patients were treated in June/July 2020 and followed for 60 days or more post ICU admission.Setting: Intensive care unit and step down units of a quaternary care hospital.Participants: 21 consecutively admitted patients with Critical COVID-19, treated with intravenous aviptadil, compared to all patients with comparable comorbidity (n=24),ICU admission sequential organ failure assessment (SOFA) score, Rothman index and WHO ordinal scale from the same ICU, treated by the same clinical team, in the same time-frame who received maximal standard of care (SOC).Intervention: 3 successive 12-hour intravenous infusions of aviptadil at 50/100/150 pmol/kg/hr.Main Outcome Measures: Survival, Recovery from Respiratory Failure, WHO 10 point ordinal scale.Results: Nineteen of 21 patients survived to day 28 in the aviptadil-treated group compared to 4 of 24 control patients (90% vs 17%;P<.0001). Kaplan-Meier analysis demonstrates a 9-fold advantage in probability of survival (Hazard Ratio 0.113;95% CL 0.037, 0.343). A similar 9-fold advantage was seen in cumulative probability of Recovery from Respiratory Failure (Hazard ratio: 0.115;95% CL: 0.0254, 0.5219). A mean 6.1 point difference in the 10 point WHO Ordinal Scale for COVID-19 was seen between aviptadil-treated patients, who exhibited a 2.6 point mean improvement from time of ICU admission vs. those treated with SOC who exhibited a mean 3.5 point mean decrement (Wilcoxon rank sum: P<.001). Improved radiographic appearance was seen in both lungs of 17 patients and in one lung of 2 treated patients. Four of 5 aviptadil-treated patients initially on Extracorporeal Membrane Oxygenation (ECMO) have been decannulated, compared to 3 of 13 ECMO-treated controls (80% vs. 23%;P=.045). A 75% (95% CI±3%: P<.001) reduction in IL-6 was seen.Comment: A dramatic multi-dimensional treatment effect was observed, consistent with FDA and ICH-10 guidance for acceptance of externally-controlled, open-label trials in high-lethality conditions. .