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నైరూప్య

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

Jihad Georges Youssef*, Jonathan C Javitt, Philip Lavin , Mukhtar Al-Saadi , Faisal Zahiruddin, Sarah Beshay, Mohammad Z. Bittar, Joseph A Kelly and Mohi U. Sayed

Importance: There is currently no meaningfully effective drug for Critical COVID-19 with respiratory failure, particularly in highly comorbid patients with mortality in excess of 30%. Vasoactive Intestinal Peptide (VIP) blocks replication of the SARSCoV-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 the survival and recovery from respiratory failure in patients with Critical COVID-19 and severe comorbidity. Design: Prospective, open label, administratively controlled trial, measuring objective endpoints only. Patients were treated in June and 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: Seventeen of 21 patients survived to day 60 in the aviptadil treated group compared to 5 of 24 control patients (81% vs 21%; P<0.0001). Kaplan-Meier analysis demonstrates a 4 fold advantage in the probability of survival (80% vs. 20%; P<.0006). The Hazard Ratio 0.149 (95% CL:0.050, 0.445). A similar 9 fold advantage was seen in the cumulative probability of Recovery from Respiratory Failure (Hazard ratio: 0.115; 95% CL: 0.0254, 0.5219). Between Day 28 and day 60 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 the time of ICU admission vs those treated with standard of care who exhibited a mean 3.5 point mean decrement (Wilcoxon rank-sum:P<0.001). Improved radiographic appearance was seen in both lungs of 17 patients and in one lung of 2 treated patients. Four of five aviptadil treated patients initially on Extracorporeal Membrane Oxygenation (ECMO) have been decannulated, compared to 3 of 13 ECMO treated controls (80% vs 23%; P=0.045). A 75% (95% CI ± 3%: P<0.001) reduction in IL-6 was seen. At day 60, a similar 5.5 fold advantage was seen in the cumulative probability of Recovery from Respiratory Failure (55% Jihad Georges Youssef1,2*, Jonathan C Javitt3,4, Philip Lavin5 , Mukhtar Al-Saadi2 , Faisal Zahiruddin2 , Sarah Beshay2 , Mohammad Z. Bittar2 , Joseph A Kelly2 and Mohi U. Sayed2 1 Department of Academic Pulmonology, Houston Methodist Research Institute, USA 2 Department of Academic Pulmonology, Houston Methodist Hospital, USA 3 Department of Academic Pulmonology, NeuroRx, Inc. Wilmington, USA 4 Department of Oncology, Johns Hopkins University School of Medicine, USA 5 Department of Academic Pulmonology, Boston Biostatistics Research Foundation, USA Corresponding author: Jihad Georges Youssef, Department of Academic Pulmonology, Houston Methodist Research Institute, USA ï?? jgyoussef@houstonmethodist.org Citation: Youssef JG, Javitt JC, Lavin P, Al-Saadi M, Zahiruddin F, et al. (2021) VIP in the Treatment of Critical Covid-19 with Respiratory Failure in Patients with Severe Comorbidity: A Prospective Externally Controlled. J Infect Dis treat. Vol.7 No.8.52 VIP in the Treatment of Critical Covid-19 with Respiratory Failure in Patients with Severe Comorbidity: A Prospective Externally Controlled trail 2021 2 This article is available in: http://infectious-diseases-and-treatment.imedpub.com/ Journal of Infectious Diseases and Treatment ISSN 2472-1093 Introduction Critical COVID-19 with Respiratory Failure in patients with advanced comorbidity is a highly lethal condition with a known mortality in excess of 70%, despite intensive care with ventilation and extracorporeal membrane oxygenation (ECMO). Remdesivir is shown to be ineffective in patients on ventilation, as have monoclonal antibodies. Convalescent plasma, steroids, and anticoagulants have yet to show effectiveness in Critical COVID-19. 50 years ago, Nature published the first report of a novel peptide discovered in the gut of patients with atypical presentation of diarrhea and flushing. Said and Mutt named it Vasoactive Intestinal Peptide (VIP). Over the subsequent 50 years, VIP has been shown to protect the lung against a broad array of caustic, immune, and infectious injuries, through its binding to the VPAC1 receptor of the Alveolar Type II cell. This is the same pulmonary cell to which the SARS-CoV-2 virus binds via the ACE2 receptor. VIP by intravenous administration has previously demonstrated effectiveness in treating ARDS related to sepsis. Promising results have been shown with inhaled administration in treating sarcoid, and pulmonary hypertension [1-10]. COVID-19 is distinct from ARDS in that it begins with alveolar collapse, caused by a failure of surfactant production, producing a unique “ground glass” appearance on radiography. Surfactant is manufactured by the ATII cells and selective viral attack on ATII cells is sufficient to produce the lethal manifestations of Critical COVID-19. Recently, VIP was shown to block replication of the SARS-CoV-2 virus in human pulmonary epithelial cells and monocytes while also demonstrating clinical improvement on radiographic and laboratory parameters. In addition to its antiviral effect, VIP protects the Alveolar Type II (ATII) cell by upregulating surfactant production, blocking apoptosis, and blocking cytokine effects. In vitro evidence suggests that human monocytes treated with VIP secrete soluble agents that further protect ATII cells via a “bystander effect”. In addition to blocking viral replication, VIP blocks cytokine synthesis and cytopathy in human pneumocytes and upregulates surfactant production [11-15]. VIP, thus, has a mechanism of action that directly addresses Mason’s articulation of the site and mechanism of viral injury to the pulmonary epithelium [6]. Aviptadil, a synthetic form of Vasoactive Intestinal Peptide (VIP) has been granted Fast Track Designation and is currently in phase 2/3 placebo controlled trials (NCT04311697) for the treatment of Critical COVID-19 with Respiratory Failure. The protocol is based on the Phase 1 ARDS data with Aviptadil [8]. It was agreed with FDA and the IRB that the most highly comorbid patients (e.g. transplant patients, those on Extracorporeal Membrane Oxygenation (ECMO), and those with malignancy or serious cardiac conditions) with a mortality expectation in excess of 70% would be excluded from randomization and treated under Expanded Access Protocol (NCT04453839). In addition, FDA guidance identifies the appropriateness of a non-randomized design in highly lethal conditions where there is the potential to observe a dramatic treatment effect [16]. In this prospective trial, consecutive patients were assigned to Aviptadil+maximal Standard of Care (SOC) vs maximal SOC alone based on their admission to the ICU by one of two pulmonary medicine teams and by the week in which they were admitted. Once admitted to the ICU, all patients were treated by the same intensivist physicians according to the same protocol. Patients and Methods Standard of Care patients were enrolled between May 23 and August 15, 2020 in the ICU’s of the Houston Methodist Hospital System (Houston, TX). Aviptadil treated patients were enrolled between June 11 and July 30, 2020. Inclusion criteria for both cases and controls are noted in Table 1. The study follows the CONSORT rules for reporting pragmatic trials (see online checklist and CONSORT diagram). The primary endpoint was survival as measured by Kaplan Meier life table, with Recovery from Respiratory Failure, WHO 10 point ordinal scale, and PaO2: FiO2 ratio while on a ventilator as secondary endpoints [17]. Human subjects’ protection was overseen by Advarra IRB, the Institutional Review Board (IRB) of the Houston Methodist vs 10%; P=0.002) at 60 days. The hazard ratio is 0.115 (95% CL: 0.0254, 0.5219). Patients treated with Aviptadil were 7 times more likely (% WHO 0-1 57.1% (12/21) for aviptadil vs 8.3% (2/24) control, P-value=%0.0008 to achieve resolution of their symptoms. 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