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.

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]