Effectiveness of ZYESAMI™ (Aviptadil) in Accelerating Recovery and Shortening Hospitalization in Critically-Ill Patients with COVID-19 Respiratory Failure: Interim Report from a Phase 2B/3 Multicenter Trial

10 Pages Posted: 1 Apr 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

Dushyantha Jayaweera

University of Miami - Miller School of Medicine

Date Written: February 28, 2021

Abstract

Background: There is currently no effective drug to treat critically-ill patients with COVID-19 Respiratory Failure. Vasoactive Intestinal Peptide (VIP) blocks intracellular replication of the SARS-CoV-2 virus, inhibits cytokine synthesis, prevents cytopathy, and upregulates surfactant production in human alveolar type II cells, which are the site of SARS-CoV-2 infection in the lung.

Purpose: To determine the safety and efficacy of intravenous ZYESAMI™ (Aviptadil; synthetic Vasoactive Intestinal Peptide) for improving recovery from respiratory failure in patients with Respiratory Failure in Critical COVID-19.

Methods: Randomized prospective double-blind placebo-controlled trial with 28 day and 60 day endpoints. Setting: Ten US-based acute care hospitals, which included 4 tertiary care teaching hospitals and 6 regional hospitals.

Participants: 196 patients with PCR+ Critical COVID-19 treated with High Flow Nasal Cannula (HFNC: n=127) Non-Invasive Ventilation (NIV: n=32) or Mechanical Ventilation (MV: n=36). Intervention: Participants were randomly allocated to intravenous aviptadil (synthetic VIP) or placebo at a 2:1 ratio, in addition to maximal standard of care (SOC). Participants received 3 successive 12-hour intravenous infusions of Aviptadil at 50/100/150 pmol/kg/hr or normal saline placebo, each day for 3 consecutive days. The main outcome measure was cumulative probability of time to recovery from respiratory failure without relapse and with survival through day 28 and through day 60. Secondary endpoints included time to ICU discharge, time to hospital discharge, NIAID ordinal scale, and survival lifetable. Analysis was by intent to treat.

Results: Overall, 91 of 131 Aviptadil-treated participants survived to day 28 compared to 47 of 65 placebo-treated patients (70.6% vs 71.7%; P=NS). Among those treated with HFNC (n=127), the main outcome measure demonstrated a trend in favor of the drug treated group (Hazard Ratio 1.53; P=.08). Participants treated in tertiary care hospitals demonstrated a greater effect (HR 1.84; P=.058). A 10 day median difference in hospital length of stay was seen in all HFNC patients (P=.006) and a thirteen day difference was seen in those treated in tertiary care centers (P=.004), with both differences favoring treatment with aviptadil. No drug-related serious adverse events were seen in either group. The only adverse event reported more frequently in drug- vs. placebo-treated participants was mild to moderate diarrhea (30% vs 1.5% P<.001), which was expected. At 28 days, a smaller percentage of Aviptadil-treated vs. placebo-treated participants remained hospitalized for respiratory failure (37% vs 51%). The study was insufficiently powered to detect differences in outcome among patients treated with non-invasive and mechanical ventilation and no differences were detected. Comment: At 28 days, Aviptadil patients treated with HFNC were 35% - 46% more likely to recover, return home, and survive to 28 days compared to placebo-treated patients, with a trend level of significance. Aviptadil patients additionally demonstrated a highly statistically significant and clinically dramatic ten day reduction in hospitalization time. Should similar findings be observed at 60 days, Emergency Use Authorization will be sought.

Note: Trial Registration: phase 2/3 placebo-controlled trials (NCT04311697)

Funding Statement: Research support was provided by the Cavendish Impact Foundation, Princeton Alumni Angels, and the Boston Biostatistics Research Foundation. Clinical trial funding was provided by NeuroRx, Inc. and Relief Therapeutics, AG

Declaration of Interests:Author Philip Lavin COI is that he is a <1% shareholder. -Author JCJ is employed by NeuroRx, Inc., a pharmaceutical company that is currently conducting clinical trials of RLF-100 in patients with COVID-19 and has a financial interest in the outcome of those clinical trials. -Author Dushyantha T. Jayaweera MD has no conflicts of interest. -Author Richard Anthony Lee, MD has no conflicts of interest. -Author JGY has no conflict of interests.

Ethics Approval Statement: Human subjects’ protection was overseen by the Advarra IRB, the Institutional Review Boards of the participating study sites, and by an independent Data Monitoring Committee. Patients enrolled in the treatment group were given informed consent in a manner approved by FDA and the IRB.

Suggested Citation

Youssef, Jihad G. and Lee, Richard and Javitt, Jonathan and Lavin, Philip and Jayaweera, Dushyantha, Effectiveness of ZYESAMI™ (Aviptadil) in Accelerating Recovery and Shortening Hospitalization in Critically-Ill Patients with COVID-19 Respiratory Failure: Interim Report from a Phase 2B/3 Multicenter Trial (February 28, 2021). Available at SSRN: https://ssrn.com/abstract=3794262 or http://dx.doi.org/10.2139/ssrn.3794262

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

Dushyantha Jayaweera

University of Miami - Miller School of Medicine ( email )

Miami, FL 33136
United States

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