The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial*

Abstract

OBJECTIVES: Respiratory failure is a lethal complication of COVID-19 that has remained resistant to drug therapy. Vasoactive intestinal peptide (VIP) is shown in nonclinical studies to upregulate surfactant production, inhibit cytokine synthesis, prevent cytopathy, and block replication of the severe acute respiratory syndrome coronavirus 2 virus in pulmonary cells. The study aims to determine whether Aviptadil (synthetic VIP) can improve survival and recovery in patients with COVID-19 respiratory failure compared with placebo and demonstrate biological effects in such patients. DESIGN: A multicenter, placebo-controlled trial. SETTING: Ten U.S. hospitals: six tertiary-care hospitals and four community hospitals. PATIENTS: A total of 196 patients with COVID-19 respiratory failure. INTERVENTIONS: Participants were randomized 2:1 to receive 3 days of IV Aviptadil or placebo. MEASUREMENTS AND MAIN RESULTS: The primary end point (alive and free from respiratory failure at day 60) did not reach statistical significance (odds ratio [OR], 1.6; 95% CI, 0.86–3.11) for patients treated with Aviptadil when controlling for baseline ventilation status as prespecified in the protocol. There was, however, a statistically significant two-fold odds of improved survival (OR, 2.0; 95% CI, 1.1–3.9) at 60 days (p = 0.035). There was significant improvement in respiratory distress ratio and reduced interleukin 6 cytokine release (p = 0.02) by day 3. Subgroup analysis identified a statistically significant likelihood of achieving primary end point among those treated with high-flow nasal oxygen at baseline (p = 0.039). Subjects on mechanical ventilation also experienced a 10-fold increased odds of survival with drug versus placebo (p = 0.031). CONCLUSIONS: The primary end point did not reach statistical significance, indicating that there was no difference between Aviptadil versus placebo. However, Aviptadil improves the likelihood of survival from respiratory failure at day 60 in critical COVID-19 across all sites of care. Given the absence of drug-related serious adverse events and acceptable safety profile, we believe the benefit versus risk for the use of Aviptadil is favorable for patient treatment.

Brief Report: Rapid Clinical Recovery From Critical Coronavirus Disease 2019 With Respiratory Failure in a Pregnant Patient Treated With IV Vasoactive Intestinal Peptide

“…The preservation of ATII cells increased pulmonary surfactant and anti-cytokine properties likely played a significant role in the dramatic recovery of this 27 weeks pregnant patient with COVID-19 ARDS, leading to full-term pregnancy and delivery of a healthy newborn. A recently published randomized clinical trial suggests that treatment with Aviptadil improves the likelihood of recovery from respiratory failure and survival at 60 days post-treatment in critically ill patients with respiratory failure caused by COVID-19 (23).…”

Aviptadil for COVID-19: A Case Study and Call to Action About the Challenges of Research During a Global Pandemic*

“…Although none of the challenges described above are new, they were all intensified by the magnitude and time pressures of the COVID-19 pandemic. The trial by Youssef et al (2) is encouraging and suggests that Aviptadil warrants consideration as another agent for patients critically ill with COVID-19. At the same time, and taking a step back from the particulars of the agent, it also opens the door to a much-needed examination of the challenges of conducting research during a pandemic.…”

“…A related challenge is that of establishing appropriate study endpoints and outcomes. Although the primary endpoint for the study by Youssef et al (2) was initially survival, it was later modified to be a composite primary outcome of being alive and free of respiratory failure. With the benefit of hindsight, this change likely resulted in the negative outcome for the primary endpoint.…”

“…In this issue of Critical Care Medicine , Youssef et al (2) share the findings from one such study: a multicenter randomized, placebo-controlled, clinical trial of IV synthetic vasoactive intestinal peptide (Aviptadil) for adults with severe COVID-19 disease. Patients requiring supplemental oxygen delivered by nasal cannula at rates not less than 20 L/min, noninvasive ventilation, or mechanical ventilation were randomized in a 2:1 ratio to either 3 days of escalating doses of IV Aviptadil or placebo.…”

“…This uncertainty, in turn, directly impacts sample size and analytic considerations. These challenges were reflected in the study by Youssef et al (2) by the multiple adjustments made in consultation with the data monitoring committee and U.S. Food and Drug Administration (FDA) to the sample size and analytic plan, including the addition of a covariate accounting for care at a tertiary versus community hospital and an increase in the target enrollment to account for improved survival among patients treated with high-flow nasal cannula. Similar challenges likely underlie the differing fates of tocilizumab and sarilumab, two FDA-approved anti–IL-6R antibodies that were both studied as a treatment for COVID-19.…”