The CHARTER-Ireland trial: Can nebulised heparin reduce acute lung injury in patients with SARS-CoV-2 requiring advanced respiratory support in Ireland: a study protocol and statistical analysis plan for a randomised control trial.
Authors: Sheehan John Robert , Caplin Padraig , Casey Siobhain , Kernan Maeve , Kelly Claire , Murphy Darragh , Alvarez-Iglesias Alberto , Giacomini Camilla , Cody Catriona , McGeary Shane , Hanley Ciara , Curley Gerard , Haren Frank Van , McNicolas Bairbre , Laffey John G. , Cosgrave David 
Published: February 2022

Abstract
• Background: COVID-19 pneumonia is associated with the development of acute respiratory distress syndrome (ARDS) displaying some typical histological features. These include diffuse alveolar damage with extensive pulmonary coagulation activation. This results in fibrin deposition in the microvasculature, leading to the formation of hyaline membranes in the air sacs. Well conducted clinical trials have found that nebulised heparin limits pulmonary fibrin deposition, attenuates progression of ARDS, hastens recovery and is safe in non-COVID ARDS. Unfractionated heparin also inactivates the SARS-CoV-2 virus and prevents entry into mammalian cells. Nebulisation of heparin may therefore limit fibrin-mediated lung injury and inhibit pulmonary infection by SARS-CoV-2. Based on these findings, we designed the CHARTER-Ireland Study, a phase 1b/2a randomised controlled study of nebulised heparin in patients requiring advanced respiratory support for COVID 19 pneumonia.• Methods: This is a multicentre, phase 1b/IIa, randomised, parallel group, open label study. The study will randomise 40 SARs-CoV-2 positive patients receiving advanced respiratory support in a critical care area. Randomisation will be via 1:1 allocation to usual care plus nebulised unfractionated heparin 6 hourly to day 10 while receiving advanced respiratory support or usual care only. The study aims to evaluate whether unfractionated heparin will decrease the procoagulant response associated with ARDS up to day 10. The study will also assess safety and tolerability of nebulised heparin as defined by number of severe adverse events; oxygen index and respiratory oxygenation index of intubated and unintubated respectively; ventilatory ratio; plasma concentration of interleukin (IL)-1β, IL6, IL-8, IL-10 and soluble tumour necrosis factor receptor 1, C-reactive protein, procalcitonin, Ferritin, Fibrinogen and lactate dehydrogenase as well as the ratios of IL-1β/IL-10 and IL-6/IL-10. These parameters will be assessed on days 1, 3, 5 and 10; time to separation from advanced respiratory support, time to discharge from the intensive care unit and number tracheostomised to day 28; survival to day 28, 60 and to hospital discharge, censored at day 60. Some clinical outcome data feeding into the CHARTER and INHALE-HEP international meta-trials.• Discussion: This trial aims to provide evidence of potential therapeutic benefit while establishing safety of nebulised heparin in the management of ARDS associated with SARs-CoV-2 infection.Trial registration: ClinicalTrials.gov, ID: NCT04511923. Registered on 13 August 2020. Protocol Version 7, 22 February 2021Protocol Identifier: NUIG-2020-003EudraCT registration number: 2020-003349-12 9 October 2020