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. 2022 Jul;88(7):3272-3287.
doi: 10.1111/bcp.15253. Epub 2022 Feb 20.

Can nebulised HepArin Reduce morTality and time to Extubation in patients with COVID-19 Requiring invasive ventilation Meta-Trial (CHARTER-MT): Protocol and statistical analysis plan for an investigator-initiated international meta-trial of prospective randomised clinical studies

Frank M P van Haren  1   2   3 , John G Laffey  4   5 , Antonio Artigas  6 , Clive Page  7 , Marcus J Schultz  8   9   10 , David Cosgrave  5 , Bairbre McNicholas  5 , Thomas L Smoot  11 , Quentin Nunes  12 , Alice Richardson  1 , Hwan-Jin Yoon  1 , Lex M van Loon  1 , Angajendra Ghosh  13 , Simone Said  13 , Rakshit Panwar  14 , Roger Smith  15 , John D Santamaria  15 , Barry Dixon  15 ; CHARTER Collaborative Research Group
Affiliations

Can nebulised HepArin Reduce morTality and time to Extubation in patients with COVID-19 Requiring invasive ventilation Meta-Trial (CHARTER-MT): Protocol and statistical analysis plan for an investigator-initiated international meta-trial of prospective randomised clinical studies

Frank M P van Haren et al. Br J Clin Pharmacol. 2022 Jul.

Abstract

There is significant interest in the potential for nebulised unfractionated heparin (UFH), as a novel therapy for patients with COVID-19 induced acute hypoxaemic respiratory failure requiring invasive ventilation. The scientific and biological rationale for nebulised heparin stems from the evidence for extensive activation of coagulation resulting in pulmonary microvascular thrombosis in COVID-19 pneumonia. Nebulised delivery of heparin to the lung may limit alveolar fibrin deposition and thereby limit progression of lung injury. Importantly, laboratory studies show that heparin can directly inactivate the SARS-CoV-2 virus, thereby prevent its entry into and infection of mammalian cells. UFH has additional anti-inflammatory and mucolytic properties that may be useful in this context. METHODS AND INTERVENTION: The Can nebulised HepArin Reduce morTality and time to Extubation in Patients with COVID-19 Requiring invasive ventilation Meta-Trial (CHARTER-MT) is a collaborative prospective individual patient data analysis of on-going randomised controlled clinical trials across several countries in five continents, examining the effects of inhaled heparin in patients with COVID-19 requiring invasive ventilation on various endpoints. Each constituent study will randomise patients with COVID-19 induced respiratory failure requiring invasive ventilation. Patients are randomised to receive nebulised heparin or standard care (open label studies) or placebo (blinded placebo-controlled studies) while under invasive ventilation. Each participating study collect a pre-defined minimum dataset. The primary outcome for the meta-trial is the number of ventilator-free days up to day 28 day, defined as days alive and free from invasive ventilation.

Keywords: ARDS; COVID-19; RCT; SARS; SARS-CoV-2; meta-trial; nebulised heparin; pandemic; randomised study; respiratory failure; unfractionated heparin.

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Conflict of interest statement

F.v.H., J.L., D.C., B.M., T.S., Q.N., E.G., A.G., S.S., R.P., R.S., J.S. and B.D. have nothing to declare. A.A. reports a research grant for preclinical research from Grifols and from Fisher&Paykel, and payment as Scientific Advisor for Grifols, outside the submitted work. C.P. reports receiving personal fees from Cipla, Immune Regulation, EpiEndo and Glycosynnovation, and has equity in Verona Pharma, outside of the submitted work.

Figures

FIGURE 1
FIGURE 1
Ventilator circuit and nebuliser set‐up
FIGURE 2
FIGURE 2
Consolidated Standards of Reporting Trials (CONSORT) diagram for CHARTER‐MT
See this image and copyright information in PMC

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