VIP in the Treatment of Critical COVID-19 With Respiratory Failure in Patients With Severe Comorbidity: A Prospective Externally-Controlled Trial

Abstract

Importance: There is currently no meaningfully effective drug for Critical COVID-19 with respiratory failure, particularly in highly comorbid patients with mortality 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 Vasoactive Intestinal Peptide) for improving the survival and recovery from respiratory failure in patients with Critical COVID-19 and severe comorbidity.

Design: Prospective, open-label, administratively-controlled trial, measuring objective endpoints only. Patients were treated in June and 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 (synthetic VIP), compared to all patients with comparable comorbidity (n=24) 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: Seventeen of 21 patients survived to day 60 in the aviptadil-treated group compared to 5 of 24 control patients (81% vs. 21%; P<.0001). Kaplan-Meier analysis demonstrates a 4-fold advantage in the probability of survival (80% vs. 20%; P<.0006). The Hazard Ratio: 0.149 (95%CL: 0.050, 0.445). Between Day 28 and day 60, 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 the time of ICU admission vs. those treated with standard of care 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 five 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.
At day 60, a similar 5.5-fold advantage was seen in the cumulative probability of Recovery from Respiratory Failure (55% vs 10%; P=.002) at 60 days . The hazard ratio is 0.115 (95% CL: 0.0254, 0.5219). Patients treated with Aviptadil were 7-times more likely (% WHO 0-1 57.1% (12/21) for aviptadil vs 8.3% (2/24) control, p-value = 0.0008) to achieve resolution of their symptoms.

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.

Note: Funding: Funding:Research support was provided by the Cavendish Impact Foundation. Clinical trial funding was provided by Relief Therapeutics Holdings, AG, Geneva, which holds intellectual property related to the pharmacologic use of Aviptadil.

Conflict of Interest: Author JCJ is employed bya pharmaceutical company that is currently conducting clinical trials of RLF-100in patients with COVID-19 and has a financial interest in the outcome of those clinical trials. Author MJJ was paid for medical writing by NeuroRx, Inc. Author JGY has received funding as an investigator for RLF-100 through his institution.

Ethical Approval: Human subjects protection was overseen by the Institutional Review Board (IRB) of the Houston Methodist Hospital.

Keywords: VIP, Zyesami, vasoactive intestinal peptide, aviptadil, SARS-CoV-2, corona virus, COVID-19, respiratory failure, IL6, ARDS