Effect of Dexamethasone in Patients With ARDS and COVID-19 - Prospective, Multi-centre, Open-label, Parallel-group, Randomized Controlled Trial (REMED Trial)

Since December 2019, Covid-19 virus has infected millions of people worldwide. A significant number of patients develop hyperinflammatory state affecting lungs, which may lead to the need of oxygen therapy. In most severe cases, acute respiratory distress syndrome (ARDS) develops and high flow oxygen therapy or invasive mechanical ventilation is necessary (Wu et al., 2020). Therapeutic options in Covid-19 associated ARDS patients remain limited and mortality is still excessive. Systemic corticosteroids have potential to limit hyperinflammatory response by modulating immune system. This effect is mediated mainly by binding to glucocorticosteroid receptor α (GRα)(Meduri et al., 2020). Their effectiveness was proved in heterogeneous ARDS patients recently (Villar et al., 2020). In patients with Covid-19 pneumonia in need for oxygen therapy or mechanical ventilation, dexamethasone 6 mg per day is currently recommended. This therapy is mandated by the results of RECOVERY trial (Horby et al., 2020). After this trial was published, three randomised trials comparing hydrocortisone (Angus et al., 2020; Dequin et al., 2020) or dexamethasone (Tomazini et al., 2020) against placebo were stopped prematurely. All these studies were included in the subsequent IPD metaanalysis (Sterne et al., 2020). However, dose of 6 mg of dexamethasone is currently being reappraised. The aforementioned study in non Covid-19 ARDS patients (Villar et al., 2020) used 20 mg of dexamethasone per day, which is roughly equivalent to the methylprednisolone regimen (1mg/kg/day) studied in early severe ARDS patients (Meduri et al., 2007). Only these moderate doses (80-100 mg of methylprednisolone, equivalent to 15-19 mg of dexamethasone) have full potential to modulate immune response by saturating GRα receptors (Meduri et al., 2020). Importantly, prematurely stopped CoDEX trial (Tomazini et al., 2020) comparing dexamethasone against placebo in Covid-ARDS patients, used initial daily dose of 20 mg of dexamethasone versus placebo.

In the light of these facts, 6 mg of dexamethasone given to COVID-19 patients with different severity of illness (WHO classification group 5-10) may miss important therapeutic potential or may prevent a potential deleterious effects of a full dose therapeutic corticosteroid. Authors hypothesize that the patients with moderate to severe ARDS undergoing mechanical ventilation may benefit from higher doses of dexamethasone (Villar et al., 2020; Tomazini et al., 2020; Meduri et al., 2007).

The primary objective of this study is to test the hypothesis that administration of dexamethasone 20 mg is superior over 6 mg in adult patients with moderate or severe ARDS due to confirmed COVID-19.

Primary endpoint: Number of ventilator-free days (VFDs) at 28 days after randomisation, defined as being alive and free from mechanical ventilation (more than 48 hours).

Secondary endpoints: