Acta Anaesthesiol Scand . Higher vs. Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial: protocol and

[tetano]

Acta Anaesthesiol Scand


. 2021 Feb 14.
doi: 10.1111/aas.13795. Online ahead of print.
Higher vs. Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial: protocol and statistical analysis plan


Marie Warrer Munch[SUP] 1 2 [/SUP], Anders Granholm[SUP] 1 2 [/SUP], Sheila Nainan Myatra[SUP] 3 [/SUP], Bharath Kumar Tirupakuzhi Vijayaraghavan[SUP] 4 5 [/SUP], Maria Cronhjort[SUP] 6 [/SUP], Rebecka Rubenson Wahlin[SUP] 6 [/SUP], Stephan M Jakob[SUP] 7 [/SUP], Luca Cioccari[SUP] 7 [/SUP], Maj-Brit N?rregaard Kjaer[SUP] 1 2 [/SUP], Gitte Kingo Vesterlund[SUP] 1 2 [/SUP], Tine Sylvest Meyhoff[SUP] 1 2 [/SUP], Marie Helleberg[SUP] 8 [/SUP], Morten Hylander M?ller[SUP] 1 2 [/SUP], Thomas Benfield[SUP] 9 [/SUP], Balasubramanian Venkatesh[SUP] 10 [/SUP], Naomi Hammond[SUP] 10 [/SUP], Sharon Micallef[SUP] 10 [/SUP], Abhinav Bassi[SUP] 5 [/SUP], Oommen John[SUP] 5 11 [/SUP], Vivekanand Jha[SUP] 5 11 12 [/SUP], Klaus Tjelle Kristiansen[SUP] 13 [/SUP], Charlotte Suppli Ulrik[SUP] 14 [/SUP], Vibeke Lind J?rgensen[SUP] 15 [/SUP], Margit Smitt[SUP] 16 [/SUP], Morten H Bestle[SUP] 17 18 [/SUP], Anne Sofie Andreasen[SUP] 19 [/SUP], Lone Musaeus Poulsen[SUP] 20 [/SUP], Bodil Steen Rasmussen[SUP] 2 21 [/SUP], Anne Craveiro Br?chner[SUP] 22 [/SUP], Thomas Str?m[SUP] 23 24 [/SUP], Anders M?ller[SUP] 25 [/SUP], Mohd Saif Khan[SUP] 26 [/SUP], Ajay Padmanaban[SUP] 4 [/SUP], Jigeeshu Vasishtha Divatia[SUP] 3 [/SUP], Sanjith Saseedharan[SUP] 27 [/SUP], Kapil Borawake[SUP] 28 [/SUP], Farhad Kapadia[SUP] 29 [/SUP], Subhal Dixit[SUP] 30 [/SUP], Rajesh Chawla[SUP] 31 [/SUP], Urvi Shukla[SUP] 32 [/SUP], Pravin Amin[SUP] 33 [/SUP], Michelle S Chew[SUP] 34 [/SUP], Christian Gluud[SUP] 35 [/SUP], Theis Lange[SUP] 36 [/SUP], Anders Perner[SUP] 1 2 [/SUP]



Affiliations

• PMID: 33583034
• DOI: 10.1111/aas.13795

Abstract

Background: The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear.
Methods: The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol.
Discussion: The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society.

 

[tetano]

Acta Anaesthesiol Scand


. 2021 Feb 14.
doi: 10.1111/aas.13793. Online ahead of print.
Higher vs. Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial: protocol for a secondary Bayesian analysis


Anders Granholm[SUP] 1 2 [/SUP], Marie Warrer Munch[SUP] 1 2 [/SUP], Sheila Nainan Myatra[SUP] 3 [/SUP], Bharath Kumar Tirupakuzhi Vijayaraghavan[SUP] 4 5 [/SUP], Maria Cronhjort[SUP] 6 [/SUP], Rebecka Rubenson Wahlin[SUP] 6 [/SUP], Stephan M Jakob[SUP] 7 [/SUP], Luca Cioccari[SUP] 7 [/SUP], Maj-Brit N?rregaard Kjaer[SUP] 1 2 [/SUP], Gitte Kingo Vesterlund[SUP] 1 2 [/SUP], Tine Sylvest Meyhoff[SUP] 1 2 [/SUP], Marie Helleberg[SUP] 8 [/SUP], Morten Hylander M?ller[SUP] 1 2 [/SUP], Thomas Benfield[SUP] 9 [/SUP], Balasubramanian Venkatesh[SUP] 10 [/SUP], Naomi Hammond[SUP] 10 [/SUP], Sharon Micallef[SUP] 10 [/SUP], Abhinav Bassi[SUP] 5 [/SUP], Oommen John[SUP] 5 11 [/SUP], Vivekanand Jha[SUP] 5 11 12 [/SUP], Klaus Tjelle Kristiansen[SUP] 13 [/SUP], Charlotte Suppli Ulrik[SUP] 14 [/SUP], Vibeke Lind J?rgensen[SUP] 15 [/SUP], Margit Smitt[SUP] 16 [/SUP], Morten H Bestle[SUP] 17 18 [/SUP], Anne Sofie Andreasen[SUP] 19 [/SUP], Lone Musaeus Poulsen[SUP] 20 [/SUP], Bodil Steen Rasmussen[SUP] 2 21 [/SUP], Anne Craveiro Br?chner[SUP] 22 [/SUP], Thomas Str?m[SUP] 23 24 [/SUP], Anders M?ller[SUP] 25 [/SUP], Mohd Saif Khan[SUP] 26 [/SUP], Ajay Padmanaban[SUP] 4 [/SUP], Jigeeshu Vasishtha Divatia[SUP] 3 [/SUP], Sanjith Saseedharan[SUP] 27 [/SUP], Kapil Borawake[SUP] 28 [/SUP], Farhad Kapadia[SUP] 29 [/SUP], Subhal Dixit[SUP] 30 [/SUP], Rajesh Chawla[SUP] 31 [/SUP], Urvi Shukla[SUP] 32 [/SUP], Pravin Amin[SUP] 33 [/SUP], Michelle S Chew[SUP] 34 [/SUP], Christian Gluud[SUP] 35 [/SUP], Theis Lange[SUP] 36 [/SUP], Anders Perner[SUP] 1 2 [/SUP]



Affiliations

• PMID: 33583027
• DOI: 10.1111/aas.13793

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.