TY - JOUR

T1 - Higher vs Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial

T2 - Protocol for a secondary Bayesian analysis

AU - Granholm, Anders

AU - Munch, Marie Warrer

AU - Myatra, Sheila Nainan

AU - Vijayaraghavan, Bharath Kumar Tirupakuzhi

AU - Cronhjort, Maria

AU - Wahlin, Rebecka Rubenson

AU - Jakob, Stephan M.

AU - Cioccari, Luca

AU - Kjær, Maj Brit Nørregaard

AU - Vesterlund, Gitte Kingo

AU - Meyhoff, Tine Sylvest

AU - Helleberg, Marie

AU - Møller, Morten Hylander

AU - Benfield, Thomas

AU - Venkatesh, Balasubramanian

AU - Hammond, Naomi

AU - Micallef, Sharon

AU - Bassi, Abhinav

AU - John, Oommen

AU - Jha, Vivekanand

AU - Kristiansen, Klaus Tjelle

AU - Ulrik, Charlotte Suppli

AU - Jørgensen, Vibeke Lind

AU - Smitt, Margit

AU - Bestle, Morten H.

AU - Andreasen, Anne Sofie

AU - Poulsen, Lone Musaeus

AU - Rasmussen, Bodil Steen

AU - Brøchner, Anne Craveiro

AU - Strøm, Thomas

AU - Møller, Anders

AU - Khan, Mohd Saif

AU - Padmanaban, Ajay

AU - Divatia, Jigeeshu Vasishtha

AU - Saseedharan, Sanjith

AU - Borawake, Kapil

AU - Kapadia, Farhad

AU - Dixit, Subhal

AU - Chawla, Rajesh

AU - Shukla, Urvi

AU - Amin, Pravin

AU - Chew, Michelle S.

AU - Gluud, Christian

AU - Lange, Theis

AU - Perner, Anders

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

U2 - 10.1111/aas.13793

DO - 10.1111/aas.13793

M3 - Journal article

C2 - 33583027

AN - SCOPUS:85101768138

VL - 65

SP - 702

EP - 710

JO - Acta Anaesthesiologica Scandinavica

JF - Acta Anaesthesiologica Scandinavica

SN - 0001-5172

IS - 5

ER -