VIP in the Treatment of Critical COVID-19 With Respiratory Failure in Patients With Severe Comorbidity: A Prospective Externally-Controlled Trial

12 Pages Posted: 4 Aug 2020 Last revised: 26 Oct 2020

See all articles by Jihad G. Youssef

Jihad G. Youssef

Houston Methodist Research Institute

Jonathan Javitt

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

Philip Lavin

Boston Biostatistical Research Foundation

Mukhtar Al-Saadi

Houston Methodist Hospital

Faisal Zahiruddin

Houston Methodist Hospital

Sarah Beshay

Houston Methodist Hospital

Mohammad Bitar

Houston Methodist Hospital

Joseph Kelley

Houston Methodist Hospital

Mohi Sayed

Houston Methodist Hospital

Multiple version iconThere are 2 versions of this paper

Date Written: October 25, 2020

Abstract

Importance: There is currently no effective drug for Critical COVID-19 with Respiratory Failure, particularly in highly comorbid patients and mortality is in excess of 30%. Vasoactive Intestinal Peptide (VIP) blocks replication of the SARS-CoV-2 virus, inhibits cytokine synthesis, prevents cytopathy, and upregulates surfactant production in human pulmonary cells.

Objective: To determine the safety and efficacy of intravenous aviptadil (synthetic Vasoactive Intestinal Peptide) for improving survival and recovery from respiratory failure in patients with Critical COVID-19 and severe comorbidity who are ineligible for phase 3 trials of aviptadil.

Design: Prospective, open-label, administratively-controlled trial, measuring objective endpoints only. Patients were treated in June/July 2020. and followed for 60 days or more post ICU admission.

Setting: Intensive care unit and step down units of a quaternary care hospital

Participants: 21 consecutively admitted patients with Critical COVID-19, treated with intravenous aviptadil (synthetic VIP), compared to all patients with comparable comorbidity (n=24) from the same ICU, treated by the same clinical team, in the same time-frame who received maximal standard of care (SOC).

Intervention: 3 successive 12-hour intravenous infusions of aviptadil at 50/100/150 pmol/kg/hr.

Main Outcome Measures: Survival, Recovery from Respiratory Failure, WHO 10 point ordinal scale. Results: Nineteen of 21 patients survived to day 28 in the aviptadil-treated group compared to 4 of 24 control patients (90% vs 17%; P<.0001). Kaplan-Meier analysis demonstrates a 9-fold advantage in probability of survival (Hazard Ratio 0.113; 95% CL 0.037, 0.343). A similar 9-fold advantage was seen in cumulative probability of Recovery from Respiratory Failure (Hazard ratio: 0.115; 95% CL: 0.0254, 0.5219). A mean 6.1 point difference in the 10 point WHO Ordinal Scale for COVID-19 was seen between aviptadil-treated patients, who exhibited a 2.6 point mean improvement from time of ICU admission vs. those treated with standard of care who exhibited a mean 3.5 point mean decrement (Wilcoxon rank sum: P<.001). Improved radiographic appearance was seen in both lungs of 17 patients and in one lung of 2 treated patients. Four of 5 aviptadil-treated patients initially on Extracorporeal Membrane Oxygenation (ECMO) have been decannulated, compared to 3 of 13 ECMO-treated controls (80% vs. 23%;P=.045). A 75% (95% CIĀ±3%: P<.001) reduction in IL-6 was seen.

Comment: A dramatic multi-dimensional treatment effect was observed, consistent with FDA and ICH-10 guidance for acceptance of externally-controlled, open-label trials in high-lethality conditions.


Note: Funding: Funding:Research support was provided by the Cavendish Impact Foundation. Clinical trial funding was provided by Relief Therapeutics Holdings, AG, Geneva, which holds intellectual property related to the pharmacologic use of Aviptadil.

Conflict of Interest: Author JCJ is employed bya pharmaceutical company that is currently conducting clinical trials of RLF-100in patients with COVID-19 and has a financial interest in the outcome of those clinical trials. Author MJJ was paid for medical writing by NeuroRx, Inc. Author JGY has received funding as an investigator for RLF-100 through his institution.

Ethical Approval: Human subjects protection was overseen by the Institutional Review Board (IRB) of the Houston Methodist Hospital.

Keywords: VIP, vasoactive intestinal peptide, aviptadil, SARS-CoV-2, corona virus, COVID-19, respiratory failure, IL6, ARDS

Suggested Citation

Youssef, Jihad G. and Javitt, Jonathan and Lavin, Philip and Al-Saadi, Mukhtar and Zahiruddin, Faisal and Beshay, Sarah and Bitar, Mohammad and Kelley, Joseph and Sayed, Mohi, VIP in the Treatment of Critical COVID-19 With Respiratory Failure in Patients With Severe Comorbidity: A Prospective Externally-Controlled Trial (October 25, 2020). Available at SSRN: https://ssrn.com/abstract=3665228 or http://dx.doi.org/10.2139/ssrn.3665228

Jihad G. Youssef

Houston Methodist Research Institute ( email )

6670 Bertner Ave
Houston, 77030
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

Mukhtar Al-Saadi

Houston Methodist Hospital

6621 Fannin St
Houston, TX 77030
United States

Faisal Zahiruddin

Houston Methodist Hospital

6621 Fannin St
Houston, TX 77030
United States

Sarah Beshay

Houston Methodist Hospital

Mohammad Bitar

Houston Methodist Hospital

Joseph Kelley

Houston Methodist Hospital ( email )

6621 Fannin St
Houston, TX 77030
United States

Mohi Sayed

Houston Methodist Hospital ( email )

6621 Fannin St
Houston, TX 77030
United States

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