Ad-hoc COVID-19 Clinical Pharmacology Task Group: Statement on dexamethasone

Clinical Pharmacology Task Group (CPTG) meeting date: June 26, 2020

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Policy question

The Public Health Agency of Canada (PHAC) asked the ad-hoc COVID-19 Clinical Pharmacology Task Group (CPTG) for advice on whether known and potential benefits of dexamethasone outweigh known and potential risks in the treatment of hospitalized COVID-19 patients receiving oxygen support.

Recommendations

The Clinical Pharmacology Task Group recommends that among hospitalized patients with COVID-19 who require supplemental oxygen or mechanical ventilation, dexamethasone 6 mg IV for 10 days (or until discharge, if earlier) or equivalent glucocorticoid dose should be strongly considered. This guidance is not meant to replace clinical judgment or specialist consultation.

This guidance will be updated as peer-reviewed evidence emerges, particularly regarding risks and benefits in older age groups, for those with different clinical presentations, and for different demographic subgroups such as sex and age.

This statement was approved by the Clinical Pharmacology Task Group on July 12, 2020.

Background

As of June 24, 2020, 14 clinical trials were registered worldwide to investigate dexamethasone as a treatment for COVID-19; none of these had treatment sites in CanadaFootnote 1. The largest study to date is the UK-based RECOVERY trial, a large randomized controlled trial testing different investigational COVID-19 therapies in hospitalized patients, including low-dose dexamethasone treatment.  

Numerous observational/retrospective studies have reported mixed clinical outcomes associated with corticosteroid treatment of COVID-19 patients. However, this may be due to the stage of disease at time of treatment.

When given during early stage COVID-19 disease, which is associated with logarithmic replication of SARS-CoV-2, anti-inflammatory properties of corticosteroids may dampen the antiviral response. This is supported by evidence of delayed viral clearance when treating SARS-CoV-2 infectionFootnote 2 as well as SARS-CoV-1 infectionFootnote 3. Corticosteroid administration during later-stage COVID-19 infection, which can be characterized by increased oxygen requirement/ICU admittance, may be beneficial in counteracting the dysregulated immune response associated with COVID-19 induced cytokine storm syndrome/acute respiratory distress syndrome (ARDS). This is supported by observational data that showed lower rates of mortality in COVID-19 patients with ARDS who received methylprednisoloneFootnote 4.

Use of corticosteroids in ARDS (all causes) is controversialFootnote 5Footnote 6Footnote 7Footnote 8Footnote 9Footnote 10Footnote 11.

Clinical evidence of efficacy to date

On June 22, 2020, Horby et al. released a preliminary report of clinical findings from the dexamethasone treatment arm of the RECOVERY trial on a pre-print website without peer review, one arm of many investigational treatment arms from the RECOVERY trial, a large randomized controlled multi-centre trial conducted at 176 NHS hospitals in the UK (n=2,104 randomized to dexamethasone; n=4,321 patients randomized to receive standard of care)Footnote 12.

Clinical evidence of safety to date

Authorization/licensure status in Canada

Considerations

Acknowledgements

This statement was prepared by:  N Forbes, M Patel, M Rieder, and M Salvadori, on behalf of the Clinical Pharmacology Task Group (CPTG).

CPTG MembersM Salvadori (Co-Chair), M Rieder (Co-chair), M Lordkipanidze, R Hall, M Piquette-Miller, A Collier and S Murthy.

CPTG gratefully acknowledges the contribution of:  N Abraham, A House, M Tunis, A Killikelly, Y Chung, J Courtemanche, A Coady, B Mitchelmore, E Chong, and R Goddard.

CPTG also gratefully acknowledges the contribution from the Canadian Agency for Drugs and Technologies in Health.

Footnotes

Footnote 1

ClinicalTrials.gov. 2020 [cited 2020 June 24]; Available from: www.clinicaltrials.gov.

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Footnote 2

Ling, Y., et al., Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients. Chin Med J (Engl), 2020. 133(9): p. 1039-1043.

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Footnote 3

Stockman, L.J., R. Bellamy, and P. Garner, SARS: systematic review of treatment effects. PLoS Med, 2006. 3(9): p. e343.

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Footnote 4

Wu, C., 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.

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Footnote 5

Annane, D., et al., Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Crit Care Med, 2017. 45(12): p. 2078-2088.

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Footnote 6

Fielding-Singh, V., M.A. Matthay, and C.S. Calfee, Beyond Low Tidal Volume Ventilation: Treatment Adjuncts for Severe Respiratory Failure in Acute Respiratory Distress Syndrome. Crit Care Med, 2018. 46(11): p. 1820-1831.

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Footnote 7

Horita, N., et al., Impact of Corticosteroids on Mortality in Patients with Acute Respiratory Distress Syndrome: A Systematic Review and Meta-analysis. Intern Med, 2015. 54(12): p. 1473-9.

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Footnote 8

Hough, C.L., Steroids for acute respiratory distress syndrome? Clin Chest Med, 2014. 35(4): p. 781-95.

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Footnote 9

Matthay, M.A., et al., Acute respiratory distress syndrome. Nat Rev Dis Primers, 2019. 5(1): p. 18.

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Footnote 10

Meduri, G.U., et al., Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature. Intensive Care Med, 2016. 42(5): p. 829-840.

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Footnote 11

Meduri, G.U., et al., Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature. Intensive Care Med, 2008. 34(1): p. 61-9.

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Footnote 12

Horby, P., et al., Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. medRxiv, 2020: p. 2020.06.22.20137273.

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Footnote 13

Yang, L., et al., A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids. Cell Stem Cell, 2020. 27(1): p. 125-136.e7.

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Footnote 14

Li, J., et al., COVID-19 infection may cause ketosis and ketoacidosis. Diabetes, Obesity and Metabolism. n/a(n/a).

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Footnote 15

Chee, Y.J., S.J.H. Ng, and E. Yeoh, Diabetic ketoacidosis precipitated by Covid-19 in a patient with newly diagnosed diabetes mellitus. Diabetes Res Clin Pract, 2020. 164: p. 108166.

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Footnote 16

Yang, J.K., et al., Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol, 2010. 47(3): p. 193-9.

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Footnote 17

Suh, S. and M.K. Park, Glucocorticoid-Induced Diabetes Mellitus: An Important but Overlooked Problem. Endocrinol Metab (Seoul), 2017. 32(2): p. 180-189.

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