Inhaled aviptadil for the possible treatment of COVID-19 in patients at high risk for ARDS: study protocol for a randomized, placebo-controlled, and multicenter trial

Maria Boesing, Kristin Abig, Michael Brändle, Martin Brutsche, Emanuel Burri, Björn C Frye, Stéphanie Giezendanner, Jan C Grutters, Philippe Haas, Justian Heisler, Fabienne Jaun, Anne B Leuppi-Taegtmeyer, Giorgia Lüthi-Corridori, Joachim Müller-Quernheim, Reto Nüesch, Wolfgang Pohl, Frank Rassouli, Jörg D Leuppi, Maria Boesing, Kristin Abig, Michael Brändle, Martin Brutsche, Emanuel Burri, Björn C Frye, Stéphanie Giezendanner, Jan C Grutters, Philippe Haas, Justian Heisler, Fabienne Jaun, Anne B Leuppi-Taegtmeyer, Giorgia Lüthi-Corridori, Joachim Müller-Quernheim, Reto Nüesch, Wolfgang Pohl, Frank Rassouli, Jörg D Leuppi

Abstract

Background: Despite the fast establishment of new therapeutic agents in the management of COVID-19 and large-scale vaccination campaigns since the beginning of the SARS-CoV-2 pandemic in early 2020, severe disease courses still represent a threat, especially to patients with risk factors. This indicates the need for alternative strategies to prevent respiratory complications like acute respiratory distress syndrome (ARDS) associated with COVID-19. Aviptadil, a synthetic form of human vasoactive intestinal peptide, might be beneficial for COVID-19 patients at high risk of developing ARDS because of its ability to influence the regulation of exaggerated pro-inflammatory proteins and orchestrate the lung homeostasis. Aviptadil has recently been shown to considerably improve the prognosis of ARDS in COVID-19 when applied intravenously. An inhaled application of aviptadil has the advantages of achieving a higher concentration in the lung tissue, fast onset of activity, avoiding the hepatic first-pass metabolism, and the reduction of adverse effects. The overall objective of this project is to assess the efficacy and safety of inhaled aviptadil in patients hospitalized for COVID-19 at high risk of developing ARDS.

Methods: This multicenter, placebo-controlled, double-blinded, randomized trial with 132 adult patients hospitalized for COVID-19 and at high risk for ARDS (adapted early acute lung injury score ≥ 2 points) is conducted in five public hospitals in Europe. Key exclusion criteria are mechanical ventilation at baseline, need for intensive care at baseline, and severe hemodynamic instability. Patients are randomly allocated to either inhale 67 μg aviptadil or normal saline (three times a day for 10 days), in addition to standard care, stratified by center. The primary endpoint is time from hospitalization to clinical improvement, defined as either hospital discharge, or improvement of at least two levels on the nine-level scale for clinical status suggested by the World Health Organization.

Discussion: Treatment strategies for COVID-19 are still limited. In the context of upcoming new variants of SARS-CoV-2 and possible inefficacy of the available vaccines and antibody therapies, the investigation of alternative therapy options plays a crucial role in decreasing associated mortality and improving prognosis. Due to its unique immunomodulating properties also targeting the SARS-CoV-2 pathways, inhaled aviptadil may have the potential to prevent ARDS in COVID-19.

Trial registration: ClinicalTrials.gov, NCT04536350 . Registered 02 September 2020.

Keywords: ARDS; Aviptadil; COVID-19; SARS-CoV-2; VIP.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Participant timeline. Asterisk symbol (*) indicates the following: if hospital discharge occurs first, intervention is stopped at discharge. Superscript digit one (1) indicates the following: demographics, clinical status according to nine-level ordinal scale, medical history, smoking status, COVID-19 symptoms, and COVID-19 vaccination status. Superscript digit two (2) indicates the following: C-reactive protein, neutrophil-lymphocyte ratio, interleukin-6, and procalcitonin. Superscript digit three (3) indicates the following: on a visual analog scale from 0 to 10. Superscript digit four (4) indicates the following: Clinical status on nine-level ordinal scale, admission to ICU, ventilation, mortality, complications. MRC, Medical Research Council dyspnea scale; SF-12v2, 12-item Short Form Survey version 2

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