Higher vs Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial: Protocol for a secondary Bayesian analysis

Abstract

Background: Coronavirus disease 2019 (COVID-19) can lead to severe hypoxic respiratory failure and death. Corticosteroids decrease mortality in severely or critically ill patients with COVID-19. However, the optimal dose remains unresolved. The ongoing randomised COVID STEROID 2 trial investigates the effects of higher vs lower doses of dexamethasone (12 vs 6 mg intravenously daily for up to 10 days) in 1,000 adult patients with COVID-19 and severe hypoxia.

Methods: This protocol outlines the rationale and statistical methods for a secondary, pre-planned Bayesian analysis of the primary outcome (days alive without life support at day 28) and all secondary outcomes registered up to day 90. We will use hurdle-negative binomial models to estimate the mean number of days alive without life support in each group and present results as mean differences and incidence rate ratios with 95% credibility intervals (CrIs). Additional count outcomes will be analysed similarly and binary outcomes will be analysed using logistic regression models with results presented as probabilities, relative risks and risk differences with 95% CrIs. We will present probabilities of any benefit/harm, clinically important benefit/harm and probabilities of effects smaller than pre-defined clinically minimally important differences for all outcomes analysed. Analyses will be adjusted for stratification variables and conducted using weakly informative priors supplemented by sensitivity analyses using sceptic priors.

Discussion: This secondary, pre-planned Bayesian analysis will supplement the primary, conventional analysis and may help clinicians, researchers and policymakers interpret the results of the COVID STEROID 2 trial while avoiding arbitrarily dichotomised interpretations of the results.

Trial registration: ClinicalTrials.gov: NCT04509973; EudraCT: 2020-003363-25.

Conflict of interest statement

Anders Perner and the Department of Intensive Care at Rigshospitalet, University of Copenhagen, has received grants for other research projects from the Novo Nordisk Foundation and Pfizer. The Department of Intensive Care Medicine, Bern University Hospital (Inselspital), has or has had research & development/consulting contracts with Edwards Lifesciences Services GmbH, Phagenesis Limited and Nestlé. The money was paid into a departmental fund, and none of the authors received any financial gain. The Department of Intensive Care Medicine, Bern University Hospital (Inselspital), has received unrestricted educational grants from the following organisations for organising bi‐annual postgraduate courses in the fields of critical care ultrasound, management of extracorporeal membrane oxygenation and mechanical ventilation: Pierre Fabre Pharma AG (formerly known as RobaPharm), Pfizer AG, Bard Medica SA, Abbott AG, Anandic Medical Systems, PanGas AG Healthcare, Orion Pharma, Bracco, Edwards Lifesciences AG, Hamilton Medical AG, Fresenius Kabi (Switzerland) AG, Getinge Group Maquet AG, Dräger Schweiz AG and Teleflex Medical GmbH. Balasubramanian Venkatesh has received institutional research support from Baxter. Thomas Benfield reports grants from Pfizer, grants from the Novo Nordisk Foundation, grants from Lundbeck Foundation, grants from Simonsen Foundation, grants and personal fees from GSK, grants and personal fees from Pfizer, personal fees from Boehringer Ingelheim, grants and personal fees from Gilead, personal fees from MSD, grants from Lundbeck Foundation and grants from Kai Hansen Foundation outside the submitted work. Tine Sylvest Meyhoff is a co‐author of a Cochrane systematic review of supplemental perioperative corticosteroids for surgical patients with adrenal insufficiency (protocol stage). Charlotte Suppli Ulrik has received personal fees, grants and/or been on advisory boards for AstraZeneca, GSK, TEVA, Orion Pharma, Actelion, Boehringer‐Ingelheim, ALK‐Abello, Novartis and Mundipharma outside the present work. The remaining authors have no conflicts of interest to declare.

© 2021 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Visualisation of results (mock figure). Mock figure illustrating how the posterior distributions for the parameters of primary interest (relative risks, risk differences, incidence rate ratios and mean differences) will be visualised. This example uses randomly generated data from a normal distribution with a mean of −3 and standard deviation of 3, simulating a potential risk difference (RD) in percentage points. In the upper subplot, the cumulative posterior distribution is visualised, corresponding to the probabilities that the RD is less than or equal to (left Y‐axis) or greater than (right Y‐axis) the effect size on the X‐axis. In the lower subplot, the entire posterior distribution is visualised, with the bold, vertical line indicating the point estimate (median value), and the area in red highlighting the percentile‐based 95% credible interval. In both subplots, the thin, black, vertical line represents no difference and the area highlighted in blue represents differences smaller than a pre‐defined clinically minimally relevant difference of 2 percentage points in either direction [Colour figure can be viewed at wileyonlinelibrary.com]