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.

Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia: a pre-planned, secondary Bayesian analysis of the COVID STEROID 2 trial

“…Here, we report the secondary, pre-planned Bayesian analyses of all outcomes registered up to day 90 in the COVID STEROID 2 trial to facilitate a more nuanced and probabilistic interpretation of the trial results [ 10 ].…”

Low‐dose hydrocortisone in patients with COVID‐19 and severe hypoxia: The COVID STEROID randomised, placebo‐controlled trial

“…Of note, the dose used was often higher than that used in the RECOVERY trial. Consequently, the higher vs lower doses of dexamethasone in patients with COVID‐19 and severe hypoxia (COVID STEROID 2) trial was commenced on 27 August 2020, to provide data on the effect of 12 mg vs 6 mg of dexamethasone in a similar cohort of patients 27,29 . In this trial, we also include patients using corticosteroids at the time of screening and patients who have limitations in the use of life‐support to increase the generalisability of the results.…”

“…In this early terminated randomised clinical trial of adult patients with COVID‐19 and severe hypoxia, we were unable to provide any precise estimates on the benefits and harms of hydrocortisone vs placebo for any outcomes as only 3% of the planned sample size had been enrolled. We did learn important lessons that have informed the design and conduct of the COVID STEROID 2 trial 27,29 …”

Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxia: an international, randomized, blinded trial

“…These potential differences may be due to differences in anti-inflammatory modulation, patient populations, outcome definitions, statistical frameworks (REMAP-CAP used Bayesian statistics) or sample sizes and event rates. Additional analyses of our trial (outcomes at day 90 and 180 and a Bayesian analysis of day 28 and 90 outcomes), 14,20 and a planned prospective meta-analysis of trials assessing higher versus standard dose dexamethasone in patients with COVID-19 and hypoxia 21 may allow more firm inferences.…”