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.

Trial registration: ClinicalTrials.gov NCT04311697.

Figure 1.

Consolidated Standards of Reporting Trials flow diagram.

Figure 2.

Respiratory distress ratio data results.

Figure 3.

Percent change cytokine interleukin 6 (IL-6) and log-IL-6 level versus baseline. A, Predicted probability of primary outcome versus change in Log IL-6 level from baseline to day 7. Increase in IL-6 at day 7 predicted >50% of the variance in treatment outcome (R² = 0.53). Treatment with Aviptadil is less likely to be associated with a day 7 increase in IL-6 and is associated with higher probability of primary end point (P < 0.001). B, Percent change from pretreatment in group cytokine IL-6 level. A significant difference is seen overall on mixed-model repeated measure between days 3 and 7 favoring Aviptadil (P = 0.024) with independent significance on days 3 (P = 0.002) and 7 (P = 0.06).