Higher vs lower doses of dexamethasone in patients with COVID‐19 and severe hypoxia (COVID STEROID 2) trial: Protocol and statistical analysis plan

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.

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

“…17 The COVID STEROID trial was paused following the preliminary results from the RECOVERY trial and afterwards terminated after publication of the WHO meta-analysis. 3,4 Additional details on the COVID STEROID 2 trial including detailed variable definitions are available in the primary protocol 9 and on the trial website (www.cric.nu/covid -stero id-2).…”

“…The primary trial protocol 9 was prepared according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement 18 ; this secondary study protocol was prepared in accordance with the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement 19 (completed checklist included in the supplement) with the Bayesian analyses specified in accordance with the Reporting Of Bayes Used in clinical STudies (ROBUST) guideline. 20 The primary trial results will be reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) statement, 21 and the results from this secondary analysis will be reported in accordance with the STROBE statement and the ROBUST guideline regardless of the results.…”

“…Shelf medication is used, and betamethasone is allowed if dexamethasone is not available. 9 To ensure blinding of clinicians, participants and outcome assessors, trial medication is prepared by unblinded trial staff not involved in patient care or outcome assessment. 9…”

“…8 The Higher vs Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial investigates the effects of 12 vs 6 mg of dexamethasone in adult patients with COVID-19 and severe hypoxia. 9 The trial will primarily be analysed using conventional, frequentist statistical methods. 9 Bayesian statistical methods are increasingly used and recommended in clinical trials in critical care as they may offer advantages or supplementary information in addition to the conventional analyses.…”

“…9 The trial will primarily be analysed using conventional, frequentist statistical methods. 9 Bayesian statistical methods are increasingly used and recommended in clinical trials in critical care as they may offer advantages or supplementary information in addition to the conventional analyses. [10][11][12][13][14][15][16] This protocol and statistical analysis plan outline the rationale and methodology for a secondary, pre-planned Bayesian analysis of the COVID STEROID 2 trial.…”