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4. Heterogeneity of treatment effect of higher dose dexamethasone by geographic region (Europe vs. India) in patients with COVID-19 and severe hypoxemia – a post hoc evaluation of the COVID STEROID 2 trial

Author

Munch, Marie W., Myatra, Sheila N., Tirupakuzhi Vijayaraghavan, Bharath Kumar, Saseedharan, Sanjith, Benfield, Thomas, Wahlin, Rebecka R., Rasmussen, Bodil S., Andreasen, Anne Sofie, Poulsen, Lone M., Cioccari, Luca, Khan, Mohd S., Kapadia, Farhad, Divatia, Jigeeshu V., Brøchner, Anne C., Bestle, Morten H., Helleberg, Marie, Michelsen, Jens, Padmanaban, Ajay, Bose, Neeta, Møller, Anders, Borawake, Kapil, Kristiansen, Klaus T., Shukla, Urvi, Chew, Michelle S., Dixit, Subhal, Ulrik, Charlotte S., Amin, Pravin R., Chawla, Rajesh, Wamberg, Christian A., Shah, Mehul S., Darfelt, Iben S., Jørgensen, Vibeke L., Smitt, Margit, Granholm, Anders, Kjær, Maj-Brit N., Møller, Morten H., Meyhoff, Tine S., Vesterlund, Gitte K., Hammond, Naomi E., Micallef, Sharon, Bassi, Abhinav, John, Oommen, Jha, Anubhuti, Cronhjort, Maria, Jakob, Stephan M., Gluud, Christian, Lange, Theis, Kadam, Vaijayanti, Marcussen, Klaus V., Hollenberg, Jacob, Hedman, Anders, Nielsen, Henrik, Schjørring, Olav L., Jensen, Marie Q., Leistner, Jens W., Jonassen, Trine B., Kristensen, Camilla M., Clapp, Esben C., Hjortsø, Carl J.S., Jensen, Thomas S., Halstad, Liv S., Bak, Emilie R.B., Zaabalawi, Reem, Metcalf-Clausen, Matias, Abdi, Suhayb, Hatley, Emma V., Aksnes, Tobias S., Gleipner-Andersen, Emil, Alarcón, A.Felix, Yamin, Gabriel, Heymowski, Adam, Berggren, Anton, la Cour, Kirstine, Weihe, Sarah, Pind, Alison H., Engstrøm, Janus, Jha, Vivekanand, Venkatesh, Balasubramanian, Perner, Anders, Hammond, Naomi, Munch, Marie Warrer, and Møller, Morten Hylander

Published
2024
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6. Long-term outcomes of dexamethasone 12 mg versus 6 mg in patients with COVID-19 and severe hypoxaemia

Author

Granholm, Anders, Kjær, Maj-Brit Nørregaard, Munch, Marie Warrer, Myatra, Sheila Nainan, Vijayaraghavan, Bharath Kumar Tirupakuzhi, Cronhjort, Maria, Wahlin, Rebecka Rubenson, Jakob, Stephan M., Cioccari, Luca, Vesterlund, Gitte Kingo, Meyhoff, Tine Sylvest, Helleberg, Marie, Møller, Morten Hylander, Benfield, Thomas, Venkatesh, Balasubramanian, Hammond, Naomi E., Micallef, Sharon, Bassi, Abhinav, John, Oommen, Jha, Vivekanand, Kristiansen, Klaus Tjelle, Ulrik, Charlotte Suppli, Jørgensen, Vibeke Lind, Smitt, Margit, Bestle, Morten H., Andreasen, Anne Sofie, Poulsen, Lone Musaeus, Rasmussen, Bodil Steen, Brøchner, Anne Craveiro, Strøm, Thomas, Møller, Anders, Khan, Mohd Saif, Padmanaban, Ajay, Divatia, Jigeeshu Vasishtha, Saseedharan, Sanjith, Borawake, Kapil, Kapadia, Farhad, Dixit, Subhal, Chawla, Rajesh, Shukla, Urvi, Amin, Pravin, Chew, Michelle S., Wamberg, Christian Aage, Bose, Neeta, Shah, Mehul S., Darfelt, Iben S., Gluud, Christian, Lange, Theis, and Perner, Anders

Published
2022
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7. 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

Author

Granholm, Anders, Munch, Marie Warrer, Myatra, Sheila Nainan, Vijayaraghavan, Bharath Kumar Tirupakuzhi, Cronhjort, Maria, Wahlin, Rebecka Rubenson, Jakob, Stephan M., Cioccari, Luca, Kjær, Maj-Brit Nørregaard, Vesterlund, Gitte Kingo, Meyhoff, Tine Sylvest, Helleberg, Marie, Møller, Morten Hylander, Benfield, Thomas, Venkatesh, Balasubramanian, Hammond, Naomi E., Micallef, Sharon, Bassi, Abhinav, John, Oommen, Jha, Vivekanand, Kristiansen, Klaus Tjelle, Ulrik, Charlotte Suppli, Jørgensen, Vibeke Lind, Smitt, Margit, Bestle, Morten H., Andreasen, Anne Sofie, Poulsen, Lone Musaeus, Rasmussen, Bodil Steen, Brøchner, Anne Craveiro, Strøm, Thomas, Møller, Anders, Khan, Mohd Saif, Padmanaban, Ajay, Divatia, Jigeeshu Vasishtha, Saseedharan, Sanjith, Borawake, Kapil, Kapadia, Farhad, Dixit, Subhal, Chawla, Rajesh, Shukla, Urvi, Amin, Pravin, Chew, Michelle S., Wamberg, Christian Aage, Gluud, Christian, Lange, Theis, and Perner, Anders

Published
2022
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10. Heterogeneity of treatment effect of higher dose dexamethasone by geographic region (Europe vs. India) in patients with COVID-19 and severe hypoxemia – a post hoc evaluation of the COVID STEROID 2 trial

Author

Tirupakuzhi Vijayaraghavan, Bharath Kumar, Granholm, Anders, Munch, Marie W., Kjær, Maj Brit N., Møller, Morten H., Perner, Anders, Myatra, Sheila N., Jha, Vivekanand, Hammond, Naomi, Micallef, Sharon, Venkatesh, Balasubramanian, Lange, Theis, Saseedharan, Sanjith, Benfield, Thomas, Wahlin, Rebecka R., Rasmussen, Bodil S., Andreasen, Anne Sofie, Poulsen, Lone M., Cioccari, Luca, Khan, Mohd S., Kapadia, Farhad, Divatia, Jigeeshu V., Brøchner, Anne C., Bestle, Morten H., Helleberg, Marie, Michelsen, Jens, Padmanaban, Ajay, Bose, Neeta, Møller, Anders, Borawake, Kapil, Kristiansen, Klaus T., Shukla, Urvi, Chew, Michelle S., Ulrik, Charlotte S., Meyhoff, Tine S., Vesterlund, Gitte K., Gluud, Christian, Marcussen, Klaus V., Nielsen, Henrik, Jensen, Thomas S., Tirupakuzhi Vijayaraghavan, Bharath Kumar, Granholm, Anders, Munch, Marie W., Kjær, Maj Brit N., Møller, Morten H., Perner, Anders, Myatra, Sheila N., Jha, Vivekanand, Hammond, Naomi, Micallef, Sharon, Venkatesh, Balasubramanian, Lange, Theis, Saseedharan, Sanjith, Benfield, Thomas, Wahlin, Rebecka R., Rasmussen, Bodil S., Andreasen, Anne Sofie, Poulsen, Lone M., Cioccari, Luca, Khan, Mohd S., Kapadia, Farhad, Divatia, Jigeeshu V., Brøchner, Anne C., Bestle, Morten H., Helleberg, Marie, Michelsen, Jens, Padmanaban, Ajay, Bose, Neeta, Møller, Anders, Borawake, Kapil, Kristiansen, Klaus T., Shukla, Urvi, Chew, Michelle S., Ulrik, Charlotte S., Meyhoff, Tine S., Vesterlund, Gitte K., Gluud, Christian, Marcussen, Klaus V., Nielsen, Henrik, and Jensen, Thomas S.

Abstract

Background In the COVID-STEROID 2 trial there was suggestion of heterogeneity of treatment effects (HTE) between patients enrolled from Europe vs. India on the primary outcome. Whether there was HTE for the remaining patient-centred outcomes is unclear. Methods In this post hoc analysis of the COVID-STEROID 2 trial, which compared 12 mg vs. 6 mg dexamethasone in adults with COVID-19 and severe hypoxemia, we evaluated HTE by geographical region (Europe vs. India) for secondary outcomes with analyses adjusted for stratification variables. Results are presented as risk differences (RDs) or mean differences (MDs) with 99% confidence intervals (CIs) and P-values from interaction tests. Findings There were differences in mortality at day 28 (RD for Europe −8.3% (99% CI: −17.7 to 1.0) vs. India 0.1% (99% CI: −10.0 to 10.0)), mortality at day 90 (RD for Europe −7.4% (99% CI: −17.1 to 2.0) vs. India −1.4% (99% CI: −12.8 to 9.8)), mortality at day 180 (RD for Europe −6.7% (99% CI: −16.4 to 2.9) vs. India −1.0% (99% CI: −12.3 to 10.3)), and number of days alive without life support at day 90 (MD for Europe 6.1 days (99% CI: −1.3 to 13.4) vs. India 1.7 days (99% CI: −8.4 to 11.8)). For serious adverse reactions, the direction was reversed (RD for Europe −1.0% (99% CI: −7.1 to 5.2) vs. India −5.3% (99% CI: −16.2 to 5.0). Interpretation Our analysis suggests higher dose dexamethasone may have less beneficial effects for patients in India as compared with those in Europe; however, the evidence is weak, and this could represent a chance finding., Background: In the COVID-STEROID 2 trial there was suggestion of heterogeneity of treatment effects (HTE) between patients enrolled from Europe vs. India on the primary outcome. Whether there was HTE for the remaining patient-centred outcomes is unclear. Methods: In this post hoc analysis of the COVID-STEROID 2 trial, which compared 12 mg vs. 6 mg dexamethasone in adults with COVID-19 and severe hypoxemia, we evaluated HTE by geographical region (Europe vs. India) for secondary outcomes with analyses adjusted for stratification variables. Results are presented as risk differences (RDs) or mean differences (MDs) with 99% confidence intervals (CIs) and P-values from interaction tests. Findings: There were differences in mortality at day 28 (RD for Europe −8.3% (99% CI: −17.7 to 1.0) vs. India 0.1% (99% CI: −10.0 to 10.0)), mortality at day 90 (RD for Europe −7.4% (99% CI: −17.1 to 2.0) vs. India −1.4% (99% CI: −12.8 to 9.8)), mortality at day 180 (RD for Europe −6.7% (99% CI: −16.4 to 2.9) vs. India −1.0% (99% CI: −12.3 to 10.3)), and number of days alive without life support at day 90 (MD for Europe 6.1 days (99% CI: −1.3 to 13.4) vs. India 1.7 days (99% CI: −8.4 to 11.8)). For serious adverse reactions, the direction was reversed (RD for Europe −1.0% (99% CI: −7.1 to 5.2) vs. India −5.3% (99% CI: −16.2 to 5.0). Interpretation: Our analysis suggests higher dose dexamethasone may have less beneficial effects for patients in India as compared with those in Europe; however, the evidence is weak, and this could represent a chance finding. Funding: None for this analysis. The COVID STEROID 2 trial was funded by The Novo Nordisk Foundation and supported by Rigshospitalet's Research Council.

Published
2024

12. Selective digestive tract decontamination in critically ill adults with acute brain injuries: a Post-Hoc analysis of a Randomized Clinical Trial.

Author

Young, Paul, primary, Devaux, Anthony, additional, Li, Qiang, additional, Billot, Laurent, additional, Davis, Joshua, additional, Delaney, Anthony, additional, Finfer, Simon, additional, Hammond, Naomi, additional, Micallef, Sharon, additional, Seppelt, Ian, additional, Venkatesh, Balasubramanian, additional, and Myburgh, John A, additional

Published
2023
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13. Heterogeneity of treatment effect of higher dose dexamethasone by geographic region (Europe vs. India) in patients with COVID-19 and severe hypoxemia – a post hoc evaluation of the COVID STEROID 2 trial

Author

Tirupakuzhi Vijayaraghavan, Bharath Kumar, primary, Granholm, Anders, additional, Myatra, Sheila N., additional, Jha, Vivekanand, additional, Hammond, Naomi, additional, Micallef, Sharon, additional, Munch, Marie Warrer, additional, Kjær, Maj-Brit N., additional, Møller, Morten Hylander, additional, Lange, Theis, additional, Perner, Anders, additional, Venkatesh, Balasubramanian, additional, Munch, Marie W., additional, Tirupakuzhi Vijayaraghavan, Bharath Kumar, additional, Saseedharan, Sanjith, additional, Benfield, Thomas, additional, Wahlin, Rebecka R., additional, Rasmussen, Bodil S., additional, Andreasen, Anne Sofie, additional, Poulsen, Lone M., additional, Cioccari, Luca, additional, Khan, Mohd S., additional, Kapadia, Farhad, additional, Divatia, Jigeeshu V., additional, Brøchner, Anne C., additional, Bestle, Morten H., additional, Helleberg, Marie, additional, Michelsen, Jens, additional, Padmanaban, Ajay, additional, Bose, Neeta, additional, Møller, Anders, additional, Borawake, Kapil, additional, Kristiansen, Klaus T., additional, Shukla, Urvi, additional, Chew, Michelle S., additional, Dixit, Subhal, additional, Ulrik, Charlotte S., additional, Amin, Pravin R., additional, Chawla, Rajesh, additional, Wamberg, Christian A., additional, Shah, Mehul S., additional, Darfelt, Iben S., additional, Jørgensen, Vibeke L., additional, Smitt, Margit, additional, Møller, Morten H., additional, Meyhoff, Tine S., additional, Vesterlund, Gitte K., additional, Hammond, Naomi E., additional, Bassi, Abhinav, additional, John, Oommen, additional, Jha, Anubhuti, additional, Cronhjort, Maria, additional, Jakob, Stephan M., additional, Gluud, Christian, additional, Kadam, Vaijayanti, additional, Marcussen, Klaus V., additional, Hollenberg, Jacob, additional, Hedman, Anders, additional, Nielsen, Henrik, additional, Schjørring, Olav L., additional, Jensen, Marie Q., additional, Leistner, Jens W., additional, Jonassen, Trine B., additional, Kristensen, Camilla M., additional, Clapp, Esben C., additional, Hjortsø, Carl J.S., additional, Jensen, Thomas S., additional, Halstad, Liv S., additional, Bak, Emilie R.B., additional, Zaabalawi, Reem, additional, Metcalf-Clausen, Matias, additional, Abdi, Suhayb, additional, Hatley, Emma V., additional, Aksnes, Tobias S., additional, Gleipner-Andersen, Emil, additional, Alarcón, A.Felix, additional, Yamin, Gabriel, additional, Heymowski, Adam, additional, Berggren, Anton, additional, la Cour, Kirstine, additional, Weihe, Sarah, additional, Pind, Alison H., additional, and Engstrøm, Janus, additional

Published
2023
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17. Statistical Analysis Plan for Balanced versus Saline trialists living systematic review individual patient and aggregated data meta-analysis of randomized controlled trials (BEST-Living Study)

Author

Zampieri, Fernando G, primary, Cavalcanti, Alexandre B, additional, Tanna, Gian Luca Di, additional, Damiani, Lucas P, additional, Hammond, Naomi E, additional, Machado, Flavia R, additional, Micallef, Sharon, additional, Myburgh, John, additional, Ramanan, Mahesh, additional, Rice, Todd W, additional, Semler, Matthew W, additional, Young, Paul J, additional, and Finfer, Simon, additional

Published
2022
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18. Statistical Analysis Plan for the COVID STEROID 2 trial assessment of subgroup effects: patients enrolled in Europe vs. India

Author

Vijayaraghavan, Bharath, Granholm, Anders, Myatra, Sheila, Jha, Vivekanand, Hammond, Naomi, Micallef, Sharon, Munch, Marie, Moeller, Morten, Lange, Theis, Perner, Anders, and Venkatesh, Baasubramanian

Subjects
Critical Care, Virus Diseases, Medicine and Health Sciences, Medical Specialties, Life Sciences, Diseases
Abstract

This document outlines the rationale and statistical analysis plan for exploring heterogeneity of treatment effects (HTE; or subgroup effects) for patients enrolled in Europe vs. those enrolled in India in the COVID STEROID 2 trial.

Published
2022
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19. 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

Author

Granholm, Anders, Munch, Marie Warrer, Myatra, Sheila Nainan, Vijayaraghavan, Bharath Kumar Tirupakuzhi, Cronhjort, Maria, Wahlin, Rebecka Rubenson, Jakob, Stephan M., Cioccari, Luca, Kjaer, Maj-Brit Norregaard, Vesterlund, Gitte Kingo, Meyhoff, Tine Sylvest, Helleberg, Marie, Moller, Morten Hylander, Benfield, Thomas, Venkatesh, Balasubramanian, Hammond, Naomi E., Micallef, Sharon, Bassi, Abhinav, John, Oommen, Jha, Vivekanand, Kristiansen, Klaus Tjelle, Ulrik, Charlotte Suppli, Jorgensen, Vibeke Lind, Smitt, Margit, Bestle, Morten H., Andreasen, Anne Sofie, Poulsen, Lone Musaeus, Rasmussen, Bodil Steen, Brochner, Anne Craveiro, Strom, Thomas, Moller, Anders, Khan, Mohd Saif, Padmanaban, Ajay, Divatia, Jigeeshu Vasishtha, Saseedharan, Sanjith, Borawake, Kapil, Kapadia, Farhad, Dixit, Subhal, Chawla, Rajesh, Shukla, Urvi, Amin, Pravin, Chew, Michelle S., Wamberg, Christian Aage, Gluud, Christian, Lange, Theis, Perner, Anders, Granholm, Anders, Munch, Marie Warrer, Myatra, Sheila Nainan, Vijayaraghavan, Bharath Kumar Tirupakuzhi, Cronhjort, Maria, Wahlin, Rebecka Rubenson, Jakob, Stephan M., Cioccari, Luca, Kjaer, Maj-Brit Norregaard, Vesterlund, Gitte Kingo, Meyhoff, Tine Sylvest, Helleberg, Marie, Moller, Morten Hylander, Benfield, Thomas, Venkatesh, Balasubramanian, Hammond, Naomi E., Micallef, Sharon, Bassi, Abhinav, John, Oommen, Jha, Vivekanand, Kristiansen, Klaus Tjelle, Ulrik, Charlotte Suppli, Jorgensen, Vibeke Lind, Smitt, Margit, Bestle, Morten H., Andreasen, Anne Sofie, Poulsen, Lone Musaeus, Rasmussen, Bodil Steen, Brochner, Anne Craveiro, Strom, Thomas, Moller, Anders, Khan, Mohd Saif, Padmanaban, Ajay, Divatia, Jigeeshu Vasishtha, Saseedharan, Sanjith, Borawake, Kapil, Kapadia, Farhad, Dixit, Subhal, Chawla, Rajesh, Shukla, Urvi, Amin, Pravin, Chew, Michelle S., Wamberg, Christian Aage, Gluud, Christian, Lange, Theis, and Perner, Anders

Published
2022

21. Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults

Author

Finfer, Simon, primary, Micallef, Sharon, additional, Hammond, Naomi, additional, Navarra, Leanlove, additional, Bellomo, Rinaldo, additional, Billot, Laurent, additional, Delaney, Anthony, additional, Gallagher, Martin, additional, Gattas, David, additional, Li, Qiang, additional, Mackle, Diane, additional, Mysore, Jayanthi, additional, Saxena, Manoj, additional, Taylor, Colman, additional, Young, Paul, additional, and Myburgh, John, additional

Published
2022
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22. Balanced Crystalloids versus Saline in Critically Ill Adults — A Systematic Review with Meta-Analysis

Author

Hammond, Naomi E., primary, Zampieri, Fernando G., additional, Di Tanna, Gian Luca, additional, Garside, Tessa, additional, Adigbli, Derick, additional, Cavalcanti, Alexandre B., additional, Machado, Flavia R., additional, Micallef, Sharon, additional, Myburgh, John, additional, Ramanan, Mahesh, additional, Rice, Todd W., additional, Semler, Matthew W., additional, Young, Paul J., additional, Venkatesh, Balasubramanian, additional, Finfer, Simon, additional, and Delaney, Anthony, additional

Published
2022
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23. Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia:The COVID STEROID 2 Randomized Trial

Author

Munch, Marie W, Myatra, Sheila N, Vijayaraghavan, Bharath Kumar Tirupakuzhi, Saseedharan, Sanjith, Benfield, Thomas, Wahlin, Rebecka R, Rasmussen, Bodil S, Andreasen, Anne Sofie, Poulsen, Lone M, Cioccari, Luca, Khan, Mohd S, Kapadia, Farhad, Divatia, Jigeeshu V, Br��chner, Anne C, Bestle, Morten H, Helleberg, Marie, Michelsen, Jens, Padmanaban, Ajay, Bose, Neeta, M��ller, Anders, Borawake, Kapil, Kristiansen, Klaus T, Shukla, Urvi, Chew, Michelle S, Dixit, Subhal, Ulrik, Charlotte S, Amin, Pravin R, Chawla, Rajesh, Wamberg, Christian A, Shah, Mehul S, Darfelt, Iben S, J��rgensen, Vibeke L, Smitt, Margit, Granholm, Anders, Kj��r, Maj-Brit N, M��ller, Morten H, Meyhoff, Tine S, Vesterlund, Gitte K, Hammond, Naomi E, Micallef, Sharon, Bassi, Abhinav, John, Oommen, Jha, Anubhuti, Cronhjort, Maria, Jakob, Stephan M, Gluud, Christian, Lange, Theis, Kadam, Vaijayanti, Marcussen, Klaus V, Hollenberg, Jacob, Hedman, Anders, Nielsen, Henrik, Schj��rring, Olav L, Jensen, Marie Q, Leistner, Jens W, Jonassen, Trine B, Kristensen, Camilla M, Clapp, Esben C, Hjorts��, Carl J S, Jensen, Thomas S, Halstad, Liv S, Bak, Emilie R B, Zaabalawi, Reem, Metcalf-Clausen, Matias, Abdi, Suhayb, Hatley, Emma V, Aksnes, Tobias S, Gleipner-Andersen, Emil, Alarc��n, Arif F, Yamin, Gabriel, Heymowski, Adam, Berggren, Anton, La Cour, Kirstine, Weihe, Sarah, Pind, Alison H, Engstr��m, Janus, Jha, Vivekanand, Venkatesh, Balasubramanian, and Perner, Anders

Subjects
Dexamethasone/administration & dosage, Male, Mycoses/etiology, medicine.medical_treatment, Dexamethasone, Hypoxemia, law.invention, Randomized controlled trial, law, medicine, Shock, Septic/etiology, Humans, Single-Blind Method, Hypoxia, 610 Medicine & health, Glucocorticoids, Aged, Mechanical ventilation, Dose-Response Relationship, Drug, Septic shock, business.industry, Hypoxia/etiology, COVID-19, Glucocorticoids/administration & dosage, General Medicine, Middle Aged, medicine.disease, Shock, Septic, Respiration, Artificial, COVID-19 Drug Treatment, Life Support Care, Dose–response relationship, Mycoses, Relative risk, Anesthesia, Life support, COVID-19/complications, Female, medicine.symptom, business, medicine.drug
Abstract

Importance A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. Objective To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. Design, Setting, and Participants A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. Interventions Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n���=���503) or 6 mg/d of intravenous dexamethasone (n���=���497) for up to 10 days. Main Outcomes and Measures The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ���1 serious adverse reactions at 28 days). Results Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P���=���.07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]). Conclusions and Relevance Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference. Trial Registration ClinicalTrials.gov Identifier: NCT04509973 and ctri.nic.in Identifier: CTRI/2020/10/028731.

Published
2021
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24. 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

Author

Granholm, Anders, primary, Munch, Marie Warrer, additional, Myatra, Sheila Nainan, additional, Vijayaraghavan, Bharath Kumar Tirupakuzhi, additional, Cronhjort, Maria, additional, Wahlin, Rebecka Rubenson, additional, Jakob, Stephan M., additional, Cioccari, Luca, additional, Kjær, Maj-Brit Nørregaard, additional, Vesterlund, Gitte Kingo, additional, Meyhoff, Tine Sylvest, additional, Helleberg, Marie, additional, Møller, Morten Hylander, additional, Benfield, Thomas, additional, Venkatesh, Balasubramanian, additional, Hammond, Naomi E., additional, Micallef, Sharon, additional, Bassi, Abhinav, additional, John, Oommen, additional, Jha, Vivekanand, additional, Kristiansen, Klaus Tjelle, additional, Ulrik, Charlotte Suppli, additional, Jørgensen, Vibeke Lind, additional, Smitt, Margit, additional, Bestle, Morten H., additional, Andreasen, Anne Sofie, additional, Poulsen, Lone Musaeus, additional, Rasmussen, Bodil Steen, additional, Brøchner, Anne Craveiro, additional, Strøm, Thomas, additional, Møller, Anders, additional, Khan, Mohd Saif, additional, Padmanaban, Ajay, additional, Divatia, Jigeeshu Vasishtha, additional, Saseedharan, Sanjith, additional, Borawake, Kapil, additional, Kapadia, Farhad, additional, Dixit, Subhal, additional, Chawla, Rajesh, additional, Shukla, Urvi, additional, Amin, Pravin, additional, Chew, Michelle S., additional, Wamberg, Christian Aage, additional, Gluud, Christian, additional, Lange, Theis, additional, and Perner, Anders, additional

Published
2021
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25. Procalcitonin Algorithm in Critically Ill Adults with Undifferentiated Infection or Suspected Sepsis. A Randomized Controlled Trial

Author

Shehabi, Yahya, Sterba, Martin, Garrett, Peter Maxwell, Rachakonda, Kanaka Sundaram, Stephens, Dianne, Harrigan, Peter, Walker, Alison, Bailey, Michael J., Johnson, Bronwyn, Millis, David, Ding, Geoff, Peake, Sandra, Wong, Helen, Thomas, Jane, Smith, Kate, Forbes, Loretta, Hardie, Miranda, Micallef, Sharon, and Fraser, John F.

Published
2014
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26. Balanced crystalloids compared to normal saline for fluid therapy in critically ill adult patients: Systematic review and meta-analysis protocol

Author

Hammond, Naomi E, primary, Zampieri, Fernando G, additional, Garside, Tessa, additional, Adigbli, Derek, additional, Di Tanna, Gian Luca, additional, Cavalcanti, Alexandre B, additional, Machado, Flavia R, additional, Micallef, Sharon, additional, Myburgh, John, additional, Ramanan, Mahesh, additional, Rice, Todd W, additional, Semler, Matthew, additional, Young, Paul J, additional, Venkatesh, Balasubramanian, additional, Finfer, Simon, additional, and Delaney, Anthony, additional

Published
2021
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27. Effect of Selective Decontamination of the Digestive Tract on Hospital Mortality in Critically Ill Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Author

Myburgh, John A., Seppelt, Ian M., Goodman, Fiona, Billot, Laurent, Correa, Maryam, Davis, Joshua S., Gordon, Anthony C., Hammond, Naomi E., Iredell, Jon, Li, Qiang, Micallef, Sharon, Miller, Jennene, Mysore, Jayanthi, Taylor, Colman, Young, Paul J., Cuthbertson, Brian H., Finfer, Simon R., and SuDDICU Investigators for the Australian and New Zealand Intensive Care Society Clinical Trials Group

Subjects
ANTIBIOTICS, CROSS infection prevention, DECONTAMINATION (From gases, chemicals, etc.), EVALUATION research, HOSPITAL mortality, CATASTROPHIC illness, GASTROINTESTINAL system, RANDOMIZED controlled trials, ARTIFICIAL respiration, INTENSIVE care units, RESEARCH, RESEARCH methodology, COMPARATIVE studies
Abstract

Importance: Whether selective decontamination of the digestive tract (SDD) reduces mortality in critically ill patients remains uncertain.Objective: To determine whether SDD reduces in-hospital mortality in critically ill adults.Design, Setting, and Participants: A cluster, crossover, randomized clinical trial that recruited 5982 mechanically ventilated adults from 19 intensive care units (ICUs) in Australia between April 2018 and May 2021 (final follow-up, August 2021). A contemporaneous ecological assessment recruited 8599 patients from participating ICUs between May 2017 and August 2021.Interventions: ICUs were randomly assigned to adopt or not adopt a SDD strategy for 2 alternating 12-month periods, separated by a 3-month interperiod gap. Patients in the SDD group (n = 2791) received a 6-hourly application of an oral paste and administration of a gastric suspension containing colistin, tobramycin, and nystatin for the duration of mechanical ventilation, plus a 4-day course of an intravenous antibiotic with a suitable antimicrobial spectrum. Patients in the control group (n = 3191) received standard care.Main Outcomes and Measures: The primary outcome was in-hospital mortality within 90 days. There were 8 secondary outcomes, including the proportion of patients with new positive blood cultures, antibiotic-resistant organisms (AROs), and Clostridioides difficile infections. For the ecological assessment, a noninferiority margin of 2% was prespecified for 3 outcomes including new cultures of AROs.Results: Of 5982 patients (mean age, 58.3 years; 36.8% women) enrolled from 19 ICUs, all patients completed the trial. There were 753/2791 (27.0%) and 928/3191 (29.1%) in-hospital deaths in the SDD and standard care groups, respectively (mean difference, -1.7% [95% CI, -4.8% to 1.3%]; odds ratio, 0.91 [95% CI, 0.82-1.02]; P = .12). Of 8 prespecified secondary outcomes, 6 showed no significant differences. In the SDD vs standard care groups, 23.1% vs 34.6% had new ARO cultures (absolute difference, -11.0%; 95% CI, -14.7% to -7.3%), 5.6% vs 8.1% had new positive blood cultures (absolute difference, -1.95%; 95% CI, -3.5% to -0.4%), and 0.5% vs 0.9% had new C difficile infections (absolute difference, -0.24%; 95% CI, -0.6% to 0.1%). In 8599 patients enrolled in the ecological assessment, use of SDD was not shown to be noninferior with regard to the change in the proportion of patients who developed new AROs (-3.3% vs -1.59%; mean difference, -1.71% [1-sided 97.5% CI, -∞ to 4.31%] and 0.88% vs 0.55%; mean difference, -0.32% [1-sided 97.5% CI, -∞ to 5.47%]) in the first and second periods, respectively.Conclusions and Relevance: Among critically ill patients receiving mechanical ventilation, SDD, compared with standard care without SDD, did not significantly reduce in-hospital mortality. However, the confidence interval around the effect estimate includes a clinically important benefit.Trial Registration: ClinicalTrials.gov Identifier: NCT02389036. [ABSTRACT FROM AUTHOR]

Published
2022
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28. Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia The COVID STEROID 2 Randomized Trial

Author

Munch, Marie W., Myatra, Sheila N., Vijayaraghavan, Bharath Kumar Tirupakuzhi, Saseedharan, Sanjith, Benfield, Thomas, Wahlin, Rebecka R., Rasmussen, Bodil S., Andreasen, Anne Sofie, Poulsen, Lone M., Cioccari, Luca, Khan, Mohd S., Kapadia, Farhad, Divatia, Jigeeshu V., Brochner, Anne C., Bestle, Morten H., Helleberg, Marie, Michelsen, Jens, Padmanaban, Ajay, Bose, Neeta, Møller, Anders, Borawake, Kapil, Kristiansen, Klaus T., Shukla, Urvi, Chew, Michelle S., Dixit, Subhal, Ulrik, Charlotte S., Amin, Pravin R., Chawla, Rajesh, Wamberg, Christian A., Shah, Mehul S., Darfelt, Iben S., Jorgensen, Vibeke L., Smitt, Margit, Granholm, Anders, Kjær, Maj-Brit N., Møller, Morten H., Meyhoff, Tine S., Vesterlund, Gitte K., Hammond, Naomi E., Micallef, Sharon, Bassi, Abhinav, John, Oommen, Jha, Anubhuti, Cronhjort, Maria, Jakob, Stephan M., Gluud, Christian, Lange, Theis, Kadam, Vaijayanti, Marcussen, Klaus V., Hollenberg, Jacob, Hedman, Anders, Nielsen, Henrik, Schjorring, Olav L., Jensen, Marie Q., Leistner, Jens W., Jonassen, Trine B., Kristensen, Camilla M., Clapp, Esben C., Hjortso, Carl J. S., Jensen, Thomas S., Halstad, Liv S., Bak, Emilie R. B., Zaabalawi, Reem, Metcalf-Clausen, Matias, Abdi, Suhayb, Hatley, Emma V., Aksnes, Tobias S., Gleipner-Andersen, Emil, Alarcon, Arif F., Yamin, Gabriel, Heymowski, Adam, Berggren, Anton, La Cour, Kirstine, Weihe, Sarah, Pind, Alison H., Engstrom, Janus, Jha, Vivekanand, Venkatesh, Balasubramanian, Perner, Anders, Munch, Marie W., Myatra, Sheila N., Vijayaraghavan, Bharath Kumar Tirupakuzhi, Saseedharan, Sanjith, Benfield, Thomas, Wahlin, Rebecka R., Rasmussen, Bodil S., Andreasen, Anne Sofie, Poulsen, Lone M., Cioccari, Luca, Khan, Mohd S., Kapadia, Farhad, Divatia, Jigeeshu V., Brochner, Anne C., Bestle, Morten H., Helleberg, Marie, Michelsen, Jens, Padmanaban, Ajay, Bose, Neeta, Møller, Anders, Borawake, Kapil, Kristiansen, Klaus T., Shukla, Urvi, Chew, Michelle S., Dixit, Subhal, Ulrik, Charlotte S., Amin, Pravin R., Chawla, Rajesh, Wamberg, Christian A., Shah, Mehul S., Darfelt, Iben S., Jorgensen, Vibeke L., Smitt, Margit, Granholm, Anders, Kjær, Maj-Brit N., Møller, Morten H., Meyhoff, Tine S., Vesterlund, Gitte K., Hammond, Naomi E., Micallef, Sharon, Bassi, Abhinav, John, Oommen, Jha, Anubhuti, Cronhjort, Maria, Jakob, Stephan M., Gluud, Christian, Lange, Theis, Kadam, Vaijayanti, Marcussen, Klaus V., Hollenberg, Jacob, Hedman, Anders, Nielsen, Henrik, Schjorring, Olav L., Jensen, Marie Q., Leistner, Jens W., Jonassen, Trine B., Kristensen, Camilla M., Clapp, Esben C., Hjortso, Carl J. S., Jensen, Thomas S., Halstad, Liv S., Bak, Emilie R. B., Zaabalawi, Reem, Metcalf-Clausen, Matias, Abdi, Suhayb, Hatley, Emma V., Aksnes, Tobias S., Gleipner-Andersen, Emil, Alarcon, Arif F., Yamin, Gabriel, Heymowski, Adam, Berggren, Anton, La Cour, Kirstine, Weihe, Sarah, Pind, Alison H., Engstrom, Janus, Jha, Vivekanand, Venkatesh, Balasubramanian, and Perner, Anders

Abstract

Importance A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. Objective To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. Design, Setting, and Participants A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. Interventions Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. Main Outcomes and Measures The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ≥1 serious adverse reactions at 28 days). Results Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86

Published
2021

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

Author

Warrer Munch, Marie, Granholm, Anders, Nainan Myatra, Sheila, Kumar Tirupakuzhi Vijayaraghavan, Bharath, Cronhjort, Maria, Rubenson Wahlin, Rebecka, Jakob, Stephan M., Cioccari, Luca, Nørregaard Kjær, Maj Brit, Kingo Vesterlund, Gitte, Sylvest Meyhoff, Tine, Helleberg, Marie, Hylander Møller, Morten, Benfield, Thomas, Venkatesh, Balasubramanian, Hammond, Naomi, Micallef, Sharon, Bassi, Abhinav, John, Oommen, Jha, Vivekanand, Tjelle Kristiansen, Klaus, Suppli Ulrik, Charlotte, Lind Jørgensen, Vibeke, Smitt, Margit, Bestle, Morten H., Sofie Andreasen, Anne, Musaeus Poulsen, Lone, Steen Rasmussen, Bodil, Craveiro Brøchner, Anne, Strøm, Thomas, Møller, Anders, Saif Khan, Mohd, Padmanaban, Ajay, Vasishtha Divatia, Jigeeshu, Saseedharan, Sanjith, Borawake, Kapil, Kapadia, Farhad, Dixit, Subhal, Chawla, Rajesh, Shukla, Urvi, Amin, Pravin, Chew, Michelle S., Gluud, Christian, Lange, Theis, Perner, Anders, Warrer Munch, Marie, Granholm, Anders, Nainan Myatra, Sheila, Kumar Tirupakuzhi Vijayaraghavan, Bharath, Cronhjort, Maria, Rubenson Wahlin, Rebecka, Jakob, Stephan M., Cioccari, Luca, Nørregaard Kjær, Maj Brit, Kingo Vesterlund, Gitte, Sylvest Meyhoff, Tine, Helleberg, Marie, Hylander Møller, Morten, Benfield, Thomas, Venkatesh, Balasubramanian, Hammond, Naomi, Micallef, Sharon, Bassi, Abhinav, John, Oommen, Jha, Vivekanand, Tjelle Kristiansen, Klaus, Suppli Ulrik, Charlotte, Lind Jørgensen, Vibeke, Smitt, Margit, Bestle, Morten H., Sofie Andreasen, Anne, Musaeus Poulsen, Lone, Steen Rasmussen, Bodil, Craveiro Brøchner, Anne, Strøm, Thomas, Møller, Anders, Saif Khan, Mohd, Padmanaban, Ajay, Vasishtha Divatia, Jigeeshu, Saseedharan, Sanjith, Borawake, Kapil, Kapadia, Farhad, Dixit, Subhal, Chawla, Rajesh, Shukla, Urvi, Amin, Pravin, Chew, Michelle S., Gluud, Christian, Lange, Theis, and Perner, Anders

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.

Published
2021

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

Author

Granholm, Anders, Munch, Marie Warrer, Myatra, Sheila Nainan, Vijayaraghavan, Bharath Kumar Tirupakuzhi, Cronhjort, Maria, Wahlin, Rebecka Rubenson, Jakob, Stephan M., Cioccari, Luca, Kjær, Maj Brit Nørregaard, Vesterlund, Gitte Kingo, Meyhoff, Tine Sylvest, Helleberg, Marie, Møller, Morten Hylander, Benfield, Thomas, Venkatesh, Balasubramanian, Hammond, Naomi, Micallef, Sharon, Bassi, Abhinav, John, Oommen, Jha, Vivekanand, Kristiansen, Klaus Tjelle, Ulrik, Charlotte Suppli, Jørgensen, Vibeke Lind, Smitt, Margit, Bestle, Morten H., Andreasen, Anne Sofie, Poulsen, Lone Musaeus, Rasmussen, Bodil Steen, Brøchner, Anne Craveiro, Strøm, Thomas, Møller, Anders, Khan, Mohd Saif, Padmanaban, Ajay, Divatia, Jigeeshu Vasishtha, Saseedharan, Sanjith, Borawake, Kapil, Kapadia, Farhad, Dixit, Subhal, Chawla, Rajesh, Shukla, Urvi, Amin, Pravin, Chew, Michelle S., Gluud, Christian, Lange, Theis, Perner, Anders, Granholm, Anders, Munch, Marie Warrer, Myatra, Sheila Nainan, Vijayaraghavan, Bharath Kumar Tirupakuzhi, Cronhjort, Maria, Wahlin, Rebecka Rubenson, Jakob, Stephan M., Cioccari, Luca, Kjær, Maj Brit Nørregaard, Vesterlund, Gitte Kingo, Meyhoff, Tine Sylvest, Helleberg, Marie, Møller, Morten Hylander, Benfield, Thomas, Venkatesh, Balasubramanian, Hammond, Naomi, Micallef, Sharon, Bassi, Abhinav, John, Oommen, Jha, Vivekanand, Kristiansen, Klaus Tjelle, Ulrik, Charlotte Suppli, Jørgensen, Vibeke Lind, Smitt, Margit, Bestle, Morten H., Andreasen, Anne Sofie, Poulsen, Lone Musaeus, Rasmussen, Bodil Steen, Brøchner, Anne Craveiro, Strøm, Thomas, Møller, Anders, Khan, Mohd Saif, Padmanaban, Ajay, Divatia, Jigeeshu Vasishtha, Saseedharan, Sanjith, Borawake, Kapil, Kapadia, Farhad, Dixit, Subhal, Chawla, Rajesh, Shukla, Urvi, Amin, Pravin, Chew, Michelle S., Gluud, Christian, Lange, Theis, and Perner, Anders

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.

Published
2021

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

Author

Munch, Marie Warrer, Granholm, Anders, Myatra, Sheila Nainan, Vijayaraghavan, Bharath Kumar Tirupakuzhi, Cronhjort, Maria, Wahlin, Rebecka Rubenson, Jakob, Stephan M., Cioccari, Luca, Kjaer, Maj-Brit Norregaard, Vesterlund, Gitte Kingo, Meyhoff, Tine Sylvest, Helleberg, Marie, Moller, Morten Hylander, Benfield, Thomas, Venkatesh, Balasubramanian, Hammond, Naomi, Micallef, Sharon, Bassi, Abhinav, John, Oommen, Jha, Vivekanand, Kristiansen, Klaus Tjelle, Ulrik, Charlotte Suppli, Jorgensen, Vibeke Lind, Smitt, Margit, Bestle, Morten H., Andreasen, Anne Sofie, Poulsen, Lone Musaeus, Rasmussen, Bodil Steen, Brochner, Anne Craveiro, Strom, Thomas, Moller, Anders, Khan, Mohd Saif, Padmanaban, Ajay, Divatia, Jigeeshu Vasishtha, Saseedharan, Sanjith, Borawake, Kapil, Kapadia, Farhad, Dixit, Subhal, Chawla, Rajesh, Shukla, Urvi, Amin, Pravin, Chew, Michelle, Gluud, Christian, Lange, Theis, Perner, Anders, Munch, Marie Warrer, Granholm, Anders, Myatra, Sheila Nainan, Vijayaraghavan, Bharath Kumar Tirupakuzhi, Cronhjort, Maria, Wahlin, Rebecka Rubenson, Jakob, Stephan M., Cioccari, Luca, Kjaer, Maj-Brit Norregaard, Vesterlund, Gitte Kingo, Meyhoff, Tine Sylvest, Helleberg, Marie, Moller, Morten Hylander, Benfield, Thomas, Venkatesh, Balasubramanian, Hammond, Naomi, Micallef, Sharon, Bassi, Abhinav, John, Oommen, Jha, Vivekanand, Kristiansen, Klaus Tjelle, Ulrik, Charlotte Suppli, Jorgensen, Vibeke Lind, Smitt, Margit, Bestle, Morten H., Andreasen, Anne Sofie, Poulsen, Lone Musaeus, Rasmussen, Bodil Steen, Brochner, Anne Craveiro, Strom, Thomas, Moller, Anders, Khan, Mohd Saif, Padmanaban, Ajay, Divatia, Jigeeshu Vasishtha, Saseedharan, Sanjith, Borawake, Kapil, Kapadia, Farhad, Dixit, Subhal, Chawla, Rajesh, Shukla, Urvi, Amin, Pravin, Chew, Michelle, Gluud, Christian, Lange, Theis, and Perner, Anders

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., Funding Agencies|Rigshospitalets Research Council [E-22703-06]; Novo Nordisk FondenNovo Nordisk Foundation [0062998]

Published
2021
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32. Higher vs Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial: Protocol for a secondary Bayesian analysis

Author

Granholm, Anders, Munch, Marie Warrer, Myatra, Sheila Nainan, Vijayaraghavan, Bharath Kumar Tirupakuzhi, Cronhjort, Maria, Wahlin, Rebecka Rubenson, Jakob, Stephan M., Cioccari, Luca, Kjaer, Maj-Brit Norregaard, Vesterlund, Gitte Kingo, Meyhoff, Tine Sylvest, Helleberg, Marie, Moller, Morten Hylander, Benfield, Thomas, Venkatesh, Balasubramanian, Hammond, Naomi, Micallef, Sharon, Bassi, Abhinav, John, Oommen, Jha, Vivekanand, Kristiansen, Klaus Tjelle, Ulrik, Charlotte Suppli, Lind Jorgensen, Vibeke, Smitt, Margit, Bestle, Morten H., Andreasen, Anne Sofie, Poulsen, Lone Musaeus, Rasmussen, Bodil Steen, Brochner, Anne Craveiro, Strom, Thomas, Moller, Anders, Khan, Mohd Saif, Padmanaban, Ajay, Divatia, Jigeeshu Vasishtha, Saseedharan, Sanjith, Borawake, Kapil, Kapadia, Farhad, Dixit, Subhal, Chawla, Rajesh, Shukla, Urvi, Amin, Pravin, Chew, Michelle S, Gluud, Christian, Lange, Theis, Perner, Anders, Granholm, Anders, Munch, Marie Warrer, Myatra, Sheila Nainan, Vijayaraghavan, Bharath Kumar Tirupakuzhi, Cronhjort, Maria, Wahlin, Rebecka Rubenson, Jakob, Stephan M., Cioccari, Luca, Kjaer, Maj-Brit Norregaard, Vesterlund, Gitte Kingo, Meyhoff, Tine Sylvest, Helleberg, Marie, Moller, Morten Hylander, Benfield, Thomas, Venkatesh, Balasubramanian, Hammond, Naomi, Micallef, Sharon, Bassi, Abhinav, John, Oommen, Jha, Vivekanand, Kristiansen, Klaus Tjelle, Ulrik, Charlotte Suppli, Lind Jorgensen, Vibeke, Smitt, Margit, Bestle, Morten H., Andreasen, Anne Sofie, Poulsen, Lone Musaeus, Rasmussen, Bodil Steen, Brochner, Anne Craveiro, Strom, Thomas, Moller, Anders, Khan, Mohd Saif, Padmanaban, Ajay, Divatia, Jigeeshu Vasishtha, Saseedharan, Sanjith, Borawake, Kapil, Kapadia, Farhad, Dixit, Subhal, Chawla, Rajesh, Shukla, Urvi, Amin, Pravin, Chew, Michelle S, Gluud, Christian, Lange, Theis, and Perner, Anders

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., Funding Agencies|Novo Nordisk FoundationNovo Nordisk Foundation [0062998]; Rigshospitalets Research Council [E-22703-06]

Published
2021
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33. Higher vs lower doses of dexamethasone in patients with COVID‐19 and severe hypoxia (COVID STEROID 2) trial: Protocol and statistical analysis plan

Author

Munch, MW, primary, Granholm, Anders, additional, Myatra, SN, additional, Vijayaraghavan, BKT, additional, Cronhjort, Maria, additional, Wahlin, RR, additional, Jakob, Stephan M., additional, Cioccari, Luca, additional, Kjær, MN, additional, Vesterlund, GK, additional, Meyhoff, TS, additional, Helleberg, Marie, additional, Møller, MH, additional, Benfield, Thomas, additional, Venkatesh, Balasubramanian, additional, Hammond, Naomi, additional, Micallef, Sharon, additional, Bassi, Abhinav, additional, John, Oommen, additional, Jha, Vivekanand, additional, Kristiansen, KT, additional, Ulrik, CS, additional, Jørgensen, VL, additional, Smitt, Margit, additional, Bestle, Morten H., additional, Andreasen, AS, additional, Poulsen, LM, additional, Rasmussen, BS, additional, Brøchner, AC, additional, Strøm, Thomas, additional, Møller, Anders, additional, Khan, MS, additional, Padmanaban, Ajay, additional, Divatia, JV, additional, Saseedharan, Sanjith, additional, Borawake, Kapil, additional, Kapadia, Farhad, additional, Dixit, Subhal, additional, Chawla, Rajesh, additional, Shukla, Urvi, additional, Amin, Pravin, additional, Chew, Michelle S., additional, Gluud, Christian, additional, Lange, Theis, additional, and Perner, Anders, additional

Published
2021
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34. Higher vs Lower Doses of Dexamethasone in Patients with COVID‐19 and Severe Hypoxia (COVID STEROID 2) trial: Protocol for a secondary Bayesian analysis

Author

Granholm, Anders, primary, Munch, Marie Warrer, additional, Myatra, Sheila Nainan, additional, Vijayaraghavan, Bharath Kumar Tirupakuzhi, additional, Cronhjort, Maria, additional, Wahlin, Rebecka Rubenson, additional, Jakob, Stephan M., additional, Cioccari, Luca, additional, Kjær, Maj‐Brit Nørregaard, additional, Vesterlund, Gitte Kingo, additional, Meyhoff, Tine Sylvest, additional, Helleberg, Marie, additional, Møller, Morten Hylander, additional, Benfield, Thomas, additional, Venkatesh, Balasubramanian, additional, Hammond, Naomi, additional, Micallef, Sharon, additional, Bassi, Abhinav, additional, John, Oommen, additional, Jha, Vivekanand, additional, Kristiansen, Klaus Tjelle, additional, Ulrik, Charlotte Suppli, additional, Jørgensen, Vibeke Lind, additional, Smitt, Margit, additional, Bestle, Morten H., additional, Andreasen, Anne Sofie, additional, Poulsen, Lone Musaeus, additional, Rasmussen, Bodil Steen, additional, Brøchner, Anne Craveiro, additional, Strøm, Thomas, additional, Møller, Anders, additional, Khan, Mohd Saif, additional, Padmanaban, Ajay, additional, Divatia, Jigeeshu Vasishtha, additional, Saseedharan, Sanjith, additional, Borawake, Kapil, additional, Kapadia, Farhad, additional, Dixit, Subhal, additional, Chawla, Rajesh, additional, Shukla, Urvi, additional, Amin, Pravin, additional, Chew, Michelle S., additional, Gluud, Christian, additional, Lange, Theis, additional, and Perner, Anders, additional

Published
2021
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35. Dexamethasone 12 mg Versus 6 mg for Patients With COVID-19 and Severe Hypoxia: An International, Randomised, Blinded Trial

Author

Warrer Munch, Marie, primary, Myatra, Sheila Nainan, additional, Kumar Tirupakuzhi Vijavaraghavan, Bharath, additional, Saseedharan, Sanjith, additional, Benfield, Thomas, additional, Rubenson Wahlin, Rebecka, additional, Steen Rasmussen, Bodil, additional, Andreasen, Anne Sofie, additional, M. Poulsen, Lone, additional, Cioccari, Luca, additional, Saif Khan, Mohd, additional, Kapadia, Farhad, additional, Divatia, Jigeeshu, additional, C. Brøncher, Anne, additional, H. Bestle, Morten, additional, Helleberg, Marie, additional, Michelsen, Jens, additional, Padmanaban, Ajay, additional, Bose, Neeta, additional, Møller, Anders, additional, Borawake, Kapil, additional, Tjelle Kristensen, Klaus, additional, Shukla, Urvi B., additional, Chew, Michelle S., additional, Dixit, Subhal, additional, Suppli Ulrik, Charlotte, additional, R. Amin, Pravin, additional, Chawla, Rajesh, additional, A. Wamberg, Christian, additional, S. Shah, Mehul, additional, S. Darfelt, Iben, additional, Lind Jørgensen, Vibeke, additional, Smitt, Margit, additional, Granholm, Anders, additional, N. Kjær, Maj-Brit, additional, Hylander Møller, Morten, additional, Sylvest Meyhoff, Tine, additional, Kingo Vesterlund, Gitte, additional, Hammond, Naomi, additional, Micallef, Sharon, additional, Bassi, Abhinav, additional, John, Oommen, additional, Jha, Anubhuti, additional, Cronhjort, Maria, additional, M. Jakob, Stephan, additional, Gluud, Christian, additional, Lange, Theis, additional, Kadam, Vaijayanti, additional, Vennick Marcussen, Klaus, additional, Hollenberg, Jacob, additional, Hedman, Anders, additional, Nielsen, Henrik, additional, L. Schjørring, Olav, additional, Qvist Jensen, Marie, additional, Wolfgang Leistner, Jens, additional, Bak Jonassen, Trine, additional, Meno Kristensen, Camilla, additional, Christensen Clapp, Esben, additional, Steensen Hjortsø, Carl Johan, additional, Steen Jensen, Thomas, additional, Sanggaard Halstad, Liv, additional, Rose Bak, Emilie, additional, Zabaalawi, Reem, additional, Metcalf-Clausen, Matias, additional, Abdi, Suhayb, additional, Victoria Hatley, Emma, additional, Aksnes, Tobias, additional, Gleipner-Andersen, Emil, additional, Alarcón, Arif F., additional, Yamin, Gabriel, additional, Heymowski, Adam, additional, Berggren, Anton, additional, La Cour, Kirstine, additional, Weihe, Sarah, additional, Holten Pind, Alison, additional, Engstrøm, Janus, additional, Jha, Vivekanand, additional, Venkatesh, Balasubramanian, additional, and Perner, Anders, additional

Published
2021
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37. Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia: The COVID STEROID 2 Randomized Trial (vol 326, pg 1807, 2021)

Author

Munch, Marie W., Myatra, Sheila N., Vijayaraghavan, Bharath Kumar Tirupakuzhi, Saseedharan, Sanjith, Benfield, Thomas, Wahlin, Rebecka R., Rasmussen, Bodil S., Andreasen, Anne Sofie, Poulsen, Lone M., Cioccari, Luca, Khan, Mohd S., Kapadia, Farhad, Divatia, Jigeeshu V., Brochner, Anne C., Bestle, Morten H., Helleberg, Marie, Michelsen, Jens, Padmanaban, Ajay, Bose, Neeta, Moller, Anders, Borawake, Kapil, Kristiansen, Klaus T., Shukla, Urvi, Chew, Michelle S., Dixit, Subhal, Ulrik, Charlotte S., Amin, Pravin R., Chawla, Rajesh, Wamberg, Christian A., Shah, Mehul S., Darfelt, Iben S., Jorgensen, Vibeke L., Smitt, Margit, Granholm, Anders, Kjaer, Maj-Brit N., Moller, Morten H., Meyhoff, Tine S., Vesterlund, Gitte K., Hammond, Naomi E., Micallef, Sharon, Bassi, Abhinav, John, Oommen, Jha, Anubhuti, Cronhjort, Maria, Jakob, Stephan M., Christian Gluud, Lange, Theis, Kadam, Vaijayanti, Marcussen, Klaus V., Hollenberg, Jacob, Hedman, Anders, Nielsen, Henrik, Schjorring, Olav L., Jensen, Marie Q., Leistner, Jens W., Jonassen, Trine B., Kristensen, Camilla M., Clapp, Esben C., Hjortso, Carl J. S., Jensen, Thomas S., Halstad, Liv S., Bak, Emilie R. B., Zaabalawi, Reem, Metcalf-Clausen, Matias, Abdi, Suhayb, Hatley, Emma V., Aksnes, Tobias S., Gleipner-Andersen, Emil, Alarcon, Arif F., Yamin, Gabriel, Heymowski, Adam, Berggren, Anton, La Cour, Kirstine, Weihe, Sarah, Pind, Alison H., Engstrom, Janus, Jha, Vivekanand, Venkatesh, Balasubramanian, and Perner, Anders

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