Intravenous Aviptadil Is Associated with Increased Recovery and Survival in Patients with COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial

17 Pages Posted: 11 May 2021 Last revised: 22 Aug 2021

See all articles by Jihad G. Youssef

Jihad G. Youssef

Houston Methodist Research Institute

Richard Lee

University of California, Irvine

Jonathan Javitt

Johns Hopkins School of Medicine; Potomac Institute for Policy Studies; NeuroRx

Philip Lavin

Boston Biostatistical Research Foundation

Rainer Lenhardt

University of Louisville School of Medicine

David J. Park

Providence St. Jude Medical Center/St. Joseph Health Care

Javier Perez Fernandez

Medical Director, Critical Care

Melvin Morganroth

Oregon Clinic

Dushyantha Jayaweera

University of Miami - Miller School of Medicine

Date Written: August 7, 2021

Abstract

Background: Respiratory failure is a lethal complication of COVID-19 that has remained resistant to drug therapy. Vasoactive Intestinal Peptide (VIP) has been granted Emergency Use Authorization and or Compassionate Care Authorization in multiple countries and is shown to upregulate surfactant production, inhibit cytokine synthesis, prevent cytopathy, and blocks replication of the SARS-CoV-2 virus in pulmonary cells. The aim of this study is to determine whether aviptadil (synthetic VIP) can improve survival and recovery in patients with COVID-19 respiratory failure compared to placebo.

Methods: A multicenter, placebo-controlled trial in 196 patients with COVID-19 respiratory failure randomized 2:1 to receive 3 days of intravenous aviptadil (synthetic VIP) or placebo. The primary endpoint was “alive and free from respiratory failure at day 60.” We additionally studied the mechanistic effect of aviptadil on blocking cytokine production and its linkage to survival and recovery from respiratory failure. Analysis was by modified intent to treat using a prespecified regression model.

Findings: When controlling for baseline severity and site of care, patients treated with aviptadil were significantly more likely to be alive and free from respiratory failure at 60 days, compared to those treated with placebo (P=.02) and demonstrated significance on numerous other clinical endpoints. Without controlling for site of care, a two-fold increased odds of survival was seen at 60 days (95% CI 1.0 – 3.9; P=.035). Biomarker analysis demonstrates that aviptadil significantly decreased the probability of an IL-6 increase relative to placebo (50% vs. 71%; p=.04) and that preventing this cytokine rise was highly correlated with survival and recovery (P<.0001) regardless of baseline severity or treatment site.

Interpretation: 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. This efficacy is supported by biomarker evidence that aviptadil prevents the rise in cytokines that are widely believed to predispose to morbidity and mortality in COVID-19.


Note: Trial Registration: NCT04311697

Funding Statement: Clinical trial funding was provided by NeuroRx, Inc. and Relief Therapeutics, AG.

Declaration of Interests: Author JCJ is employed by NeuroRx, Inc. and is a shareholder in NeuroRx. Author PL is employed by Lavin Statistical Associates, which is paid by NeuroRx, Inc. for independent statistical analysis. Author MJM is a consultant to NeuroRx, Inc. Authors JGY, RAL, RL, DJP, JPF, and DJ received research support from NeuroRx via payments to their institutions.

Ethics Approval Statement: Clinicaltrials.gov documents approval by the Advarra IRB and each local IRB approved as well. Advarra IRB approval number: Pro00043143. Address:

Keywords: Aviptadil, COVID-19, Respiratory Failure, VIP, Vasoactive Intestinal Peptide, ZYESAMI

Suggested Citation

Youssef, Jihad G. and Lee, Richard and Javitt, Jonathan and Lavin, Philip and Lenhardt, Rainer and Park, David J and Perez Fernandez, Javier and Morganroth, Melvin and Jayaweera, Dushyantha, Intravenous Aviptadil Is Associated with Increased Recovery and Survival in Patients with COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial (August 7, 2021). Available at SSRN: https://ssrn.com/abstract=3830051 or http://dx.doi.org/10.2139/ssrn.3830051

Jihad G. Youssef

Houston Methodist Research Institute ( email )

6670 Bertner Ave
Houston, 77030
United States

Richard Lee

University of California, Irvine ( email )

Irvine, CA 92697
United States

Jonathan Javitt (Contact Author)

Johns Hopkins School of Medicine ( email )

Baltimore, MD

Potomac Institute for Policy Studies ( email )

901 N. Stuart Street
Suite 200
Arlington, VA 22203
United States

NeuroRx ( email )

NeuroRx, Inc.
913 N. Market Street
Wilmington, DE 19801
United States

HOME PAGE: http://www.neurorxpharma.com

Philip Lavin

Boston Biostatistical Research Foundation ( email )

3 Cahill Drive
Framingham, MA 01702
United States

Rainer Lenhardt

University of Louisville School of Medicine ( email )

550 South Jackson Street
Louisville, KY 40202
United States

David J Park

Providence St. Jude Medical Center/St. Joseph Health Care ( email )

101 E Valencia Mesa Dr
Fullerton, CA 92835
United States

Javier Perez Fernandez

Medical Director, Critical Care ( email )

1691 Michigan Avenue
Fifth Floor
South Miami, FL 33139
United States

Melvin Morganroth

Oregon Clinic ( email )

Portland, OR
United States

Dushyantha Jayaweera

University of Miami - Miller School of Medicine ( email )

Miami, FL 33136
United States

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