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

doi:10.1111/aas.13795

Comparative Study

. 2021 Jul;65(6):834-845.

doi: 10.1111/aas.13795. Epub 2021 Mar 9.

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

M W Munch^{1

2}, Anders Granholm^{1

2}, S N Myatra³, Bkt Vijayaraghavan^{4

5

6}, Maria Cronhjort⁷, R R Wahlin⁷, Stephan M Jakob⁸, Luca Cioccari⁸, M N Kjaer^{1

2}, G K Vesterlund^{1

2}, T S Meyhoff^{1

2}, Marie Helleberg⁹, M H Møller^{1

2}, Thomas Benfield¹⁰, Balasubramanian Venkatesh¹¹, Naomi Hammond¹¹, Sharon Micallef¹¹, Abhinav Bassi⁶, Oommen John^{6

12}, Vivekanand Jha^{6

12

13}, K T Kristiansen¹⁴, C S Ulrik¹⁵, V L Jørgensen¹⁶, Margit Smitt¹⁷, Morten H Bestle^{18

19}, A S Andreasen²⁰, L M Poulsen²¹, B S Rasmussen^{2

22}, A C Brøchner²³, Thomas Strøm^{24

25}, Anders Møller²⁶, M S Khan²⁷, Ajay Padmanaban^{4

5}, J V Divatia³, Sanjith Saseedharan²⁸, Kapil Borawake²⁹, Farhad Kapadia³⁰, Subhal Dixit³¹, Rajesh Chawla³², Urvi Shukla³³, Pravin Amin³⁴, Michelle S Chew³⁵, Christian Gluud³⁶, Theis Lange³⁷, Anders Perner^{1

2}

Affiliations

¹ Department of Intensive Care, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
² Collaboration for Research in Intensive Care (CRIC), Copenhagen, Denmark.
³ Department of Anaesthesia, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India.
⁴ Department of Critical Care, Apollo Hospitals, Chennai, India.
⁵ Chennai Critical Care Consultants, Chennai, India.
⁶ The George Institute for Global Health, University of New South Wales, New Delhi, India.
⁷ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
⁸ Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁹ Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
¹⁰ Department of Infectious Diseases, Center of Research & Disruption of Infectious Diseases, Copenhagen University Hospital - Amager and Hvidovre, Copenhagen, Denmark.
¹¹ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
¹² Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, India.
¹³ School of Public Health, Imperial College London, London, UK.
¹⁴ Department of Anaesthesia and Intensive Care, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark.
¹⁵ Department of Respiratory Medicine, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark.
¹⁶ Department of Thoracic Anaesthesiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
¹⁷ Department of Neuroanaesthesiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
¹⁸ Department of Anaesthesiology and Intensive Care, Copenhagen University Hospital, Nordsjaelland, Denmark.
¹⁹ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
²⁰ Department of Anaesthesia and Intensive Care, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
²¹ Department of Anaesthesiology, Zealand University Hospital, Copenhagen, Denmark.
²² Department of Anaesthesia and Intensive Care, Aalborg University Hospital, Aalborg, Denmark.
²³ Department of Anaesthesia and Intensive Care, Kolding Hospital, Kolding, Denmark.
²⁴ Department of Anaesthesia and Critical Care Medicine, Odense University Hospital, Odense C, Denmark.
²⁵ Department of Anaesthesia and Critical Care Medicine, Hospital Sønderjylland, University Hospital of Southern Denmark, Odense, Denmark.
²⁶ Department of Anaesthesia and Intensive Care, Naestved-Slagelse-Ringsted Hospital, Slagelse, Denmark.
²⁷ Department of Critical Care Medicine, Rajendra Institute of Medical Sciences, Ranchi, India.
²⁸ Department of Intensive Care, SL Raheja Hospital, Mumbai, Maharashtra, India.
²⁹ Department of Intensive Care, Vishwaraj Hospital, Pune, India.
³⁰ Section of Critical Care, Department of Medicine, Hinduja Hospital, Mahim, Mumbai, India.
³¹ Department of Critical Care Medicine, Sanjeevan Hospital, Pune, Maharashtra, India.
³² Department of Respiratory and Critical Care Medicine, Indraprastha Apollo Hospital, New Delhi, India.
³³ Intensive Care Unit and Emergency Services, Symbiosis University Hospital and Research Centre, Lavale, Pune, India.
³⁴ Department of Critical Care Medicine, Bombay Hospital Institute of Medical Sciences, Mumbai, India.
³⁵ Department of Anesthesiology and Intensive Care, Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
³⁶ Copenhagen Trial Unit, Centre for Clinical Intervention Research, Capital Region of Denmark, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
³⁷ Department of Public Health, Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark.

PMID: 33583034
PMCID: PMC8014264
DOI: 10.1111/aas.13795

Comparative Study

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

M W Munch et al. Acta Anaesthesiol Scand. 2021 Jul.

. 2021 Jul;65(6):834-845.

doi: 10.1111/aas.13795. Epub 2021 Mar 9.

Authors

Affiliations

¹ Department of Intensive Care, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
² Collaboration for Research in Intensive Care (CRIC), Copenhagen, Denmark.
³ Department of Anaesthesia, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India.
⁴ Department of Critical Care, Apollo Hospitals, Chennai, India.
⁵ Chennai Critical Care Consultants, Chennai, India.
⁶ The George Institute for Global Health, University of New South Wales, New Delhi, India.
⁷ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
⁸ Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁹ Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
¹⁰ Department of Infectious Diseases, Center of Research & Disruption of Infectious Diseases, Copenhagen University Hospital - Amager and Hvidovre, Copenhagen, Denmark.
¹¹ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
¹² Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, India.
¹³ School of Public Health, Imperial College London, London, UK.
¹⁴ Department of Anaesthesia and Intensive Care, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark.
¹⁵ Department of Respiratory Medicine, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark.
¹⁶ Department of Thoracic Anaesthesiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
¹⁷ Department of Neuroanaesthesiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
¹⁸ Department of Anaesthesiology and Intensive Care, Copenhagen University Hospital, Nordsjaelland, Denmark.
¹⁹ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
²⁰ Department of Anaesthesia and Intensive Care, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
²¹ Department of Anaesthesiology, Zealand University Hospital, Copenhagen, Denmark.
²² Department of Anaesthesia and Intensive Care, Aalborg University Hospital, Aalborg, Denmark.
²³ Department of Anaesthesia and Intensive Care, Kolding Hospital, Kolding, Denmark.
²⁴ Department of Anaesthesia and Critical Care Medicine, Odense University Hospital, Odense C, Denmark.
²⁵ Department of Anaesthesia and Critical Care Medicine, Hospital Sønderjylland, University Hospital of Southern Denmark, Odense, Denmark.
²⁶ Department of Anaesthesia and Intensive Care, Naestved-Slagelse-Ringsted Hospital, Slagelse, Denmark.
²⁷ Department of Critical Care Medicine, Rajendra Institute of Medical Sciences, Ranchi, India.
²⁸ Department of Intensive Care, SL Raheja Hospital, Mumbai, Maharashtra, India.
²⁹ Department of Intensive Care, Vishwaraj Hospital, Pune, India.
³⁰ Section of Critical Care, Department of Medicine, Hinduja Hospital, Mahim, Mumbai, India.
³¹ Department of Critical Care Medicine, Sanjeevan Hospital, Pune, Maharashtra, India.
³² Department of Respiratory and Critical Care Medicine, Indraprastha Apollo Hospital, New Delhi, India.
³³ Intensive Care Unit and Emergency Services, Symbiosis University Hospital and Research Centre, Lavale, Pune, India.
³⁴ Department of Critical Care Medicine, Bombay Hospital Institute of Medical Sciences, Mumbai, India.
³⁵ Department of Anesthesiology and Intensive Care, Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
³⁶ Copenhagen Trial Unit, Centre for Clinical Intervention Research, Capital Region of Denmark, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
³⁷ Department of Public Health, Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark.

PMID: 33583034
PMCID: PMC8014264
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.

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Conflict of interest statement

Anders Perner and the Department of Intensive Care at Rigshospitalet, University of Copenhagen, has received grants for other research projects from the Novo Nordisk Foundation and Pfizer. The Department of Intensive Care Medicine, Bern University Hospital (Inselspital), has or has had research & development/consulting contracts with Edwards Lifesciences Services GmbH, Phagenesis Limited and Nestlé. The money was paid into a departmental fund, and none of the authors received any financial gain. The Department of Intensive Care Medicine, Bern University Hospital (Inselspital), has received unrestricted educational grants from the following organisations for organising bi‐annual postgraduate courses in the fields of critical care ultrasound, management of extracorporeal membrane oxygenation and mechanical ventilation: Pierre Fabre Pharma AG (formerly known as RobaPharm), Pfizer AG, Bard Medica SA, Abbott AG, Anandic Medical Systems, PanGas AG Healthcare, Orion Pharma, Bracco, Edwards Lifesciences AG, Hamilton Medical AG, Fresenius Kabi (Switzerland) AG, Getinge Group Maquet AG, Dräger Schweiz AG, and Teleflex Medical GmbH. Balasubramanian Venkatesh has received institutional research support from Baxter. Thomas Benfield reports grants from Pfizer, grants from the Novo Nordisk Foundation, grants from Lundbeck Foundation, grants from Simonsen Foundation, grants and personal fees from GSK, grants and personal fees from Pfizer, personal fees from Boehringer Ingelheim, grants and personal fees from Gilead, personal fees from MSD, grants from Lundbeck Foundation, and grants from Kai Hansen Foundation outside the submitted work. Tine Sylvest Meyhoff is a co‐author of a Cochrane systematic review of supplemental perioperative corticosteroids for surgical patients with adrenal insufficiency (protocol stage). Charlotte Suppli Ulrik has received personal fees, grants and/or been on advisory boards for AstraZeneca, GSK, TEVA, Orion Pharma, Actelion, Boehringer Ingelheim, ALK‐Abello, Novartis and Mundipharma outside the present work. The remaining authors have no conflicts of interest to declare.

Figures

**FIGURE 1**
Dose preferences in corticosteroid use for COVID‐19 patients among 240 survey responders from Denmark, Sweden, Switzerland and India. In the survey, all dose options were stated as equivalents of dexamethasone, betamethasone, hydrocortisone, methylprednisolone and prednisone. COVID‐19, coronavirus disease 19; DXM, dexamethasone; mg, milligrams

**FIGURE 2**
Preferences in comparisons for future trial in COVID‐19 patients among 237 responders from Denmark, Sweden, Switzerland and India. Survey responders were able to tick one or more comparisons. COVID‐19, coronavirus disease 19, DXM, dexamethasone, mg, milligrams, HCT, hydrocortisone; PLB, placebo.

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References

1. Center for Systems Science and Engineering at Johns Hopkins University . Coronavirus COVID‐19 Global Cases. Available from: https://www.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd4029942.... Accessed on March 18 2020.
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[1] Center for Systems Science and Engineering at Johns Hopkins University . Coronavirus COVID‐19 Global Cases. Available from: https://www.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd4029942.... Accessed on March 18 2020.

[2] Center for Systems Science and Engineering at Johns Hopkins University . Coronavirus COVID‐19 Global Cases. Available from: https://www.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd4029942.... Accessed on March 18 2020.

[3] Merad M, Martin JC. Pathological inflammation in patients with COVID‐19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020;20:355‐362. - PMC - PubMed

[4] Merad M, Martin JC. Pathological inflammation in patients with COVID‐19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020;20:355‐362. - PMC - PubMed

[5] Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934. - PMC - PubMed

[6] Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934. - PMC - PubMed

[7] Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID‐19 in Wuhan, China: A retrospective cohort study. Lancet. 2020;395(10229):1054‐1062. - PMC - PubMed

[8] Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID‐19 in Wuhan, China: A retrospective cohort study. Lancet. 2020;395(10229):1054‐1062. - PMC - PubMed

[9] Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus‐infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061. - PMC - PubMed

[10] Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus‐infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061. - PMC - PubMed

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

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

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