TY - JOUR
T1 - The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure
T2 - Results of a 60-Day Randomized Controlled Trial∗
AU - Youssef, Jihad Georges
AU - Lavin, Philip
AU - Schoenfeld, David A.
AU - Lee, Richard A.
AU - Lenhardt, Rainer
AU - Park, David J.
AU - Fernandez, Javier Perez
AU - Morganroth, Melvin L.
AU - Javitt, Jonathan C.
AU - Jayaweera, Dushyantha
N1 - Funding Information:
Drs. Youssef, Lee, Lenhardt, Park, Fernandez, and Jayaweera are employed by institutions that received research support funding from NRx Pharmaceuticals. Drs. Morganroth and Lavin are consultants to NRx Pharmaceuticals. Drs. Youssef, Lee, Lenhardt, Morganroth, and Javitt disclosed the off-label product use of Vasoactive intestinal Peptide Aviptadil. Dr. Lavin’s institution received funding from NRx Pharmaceuticals. Drs. Lavin, Schoenfeld, and Javitt received funding from NRx Pharmaceuticals. Dr. Schoenfeld received funding from Immunity Pharma; he disclosed that he has consulted with external entities unrelated to this work. Drs. Schoenfeld and Javitt disclosed work for hire. Drs. Lenhardt’s, Morganroth’s, and Jayaweera’s institutions received funding from NeuroRX. Dr. Lenhardt received funding from Merck, CSL Behring, and Trevena. Dr. Fernandez received funding from NRx Consulting. Dr. Javitt disclosed that he is an employee and shareholder of NRx Pharmaceuticals and that his spouse and children have beneficial ownership in the stock of NRx Pharmaceuticals. Dr. Jayaweera’s institution received funding from Gilead Pharmaceuticals, VIIV, and Janssen; he received support for article research from the National Institutes of Health.
Publisher Copyright:
© 2022 Lippincott Williams and Wilkins. All rights reserved.
PY - 2022/11/1
Y1 - 2022/11/1
N2 - 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.
AB - 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.
KW - COVID-19
KW - acute lung injury
KW - acute respiratory distress syndrome
KW - alveolar type II
KW - coronavirus
KW - severe acute respiratory syndrome coronavirus 2
KW - surfactant
KW - vasoactive intestinal peptide
KW - Surface-Active Agents
KW - Oxygen
KW - COVID-19 Drug Treatment
KW - Humans
KW - Respiratory Insufficiency/drug therapy
KW - Interleukin-6
KW - Vasoactive Intestinal Peptide/therapeutic use
KW - Phentolamine
KW - Drug Combinations
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U2 - 10.1097/CCM.0000000000005660
DO - 10.1097/CCM.0000000000005660
M3 - Article
C2 - 36044317
AN - SCOPUS:85140024749
SN - 0090-3493
VL - 50
SP - 1545
EP - 1554
JO - Critical Care Medicine
JF - Critical Care Medicine
IS - 11
ER -