Higher vs. Lower Doses of Dexamethasone for COVID-19 and Severe Hypoxia

Study Overview
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Brief Summary
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We aim to assess the benefits and harms of higher (12 mg) vs lower doses (6 mg) of dexamethasone on patient-centered outcomes in patients with COVID-19 and severe hypoxia.

Detailed Description
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Background: Preliminary results from the Randomised Evaluation of COVid-19 thERapY (RECOVERY) trial have reported a reduction in 28-day mortality with low-dose dexamethasone (6 mg) once daily versus no intervention in hospitalised patients with COVID-19; an effect that may have been more pronounced in patients with increasing hypoxia. Yet, higher doses of dexamethasone may be beneficial in patients with non-COVID-19 acute respiratory distress syndrome. At present, it is unclear what dose of dexamethasone is most beneficial in patients with COVID-19 and severe hypoxia, and clinical equipoise exists. Objective: We aim to assess the effects of higher (12 mg) vs lower doses (6 mg) of intravenous dexamethasone on the number of days alive without life-support in adult patients with COVID-19 and severe hypoxia. Design: International, parallel-group, centrally randomised, stratified, blinded, clinical trial. Population: Adult patients with documented COVID-19 receiving at least 10 L/min of oxygen independent of delivery system OR mechanical ventilation. Experimental intervention: Dexamethasone 12 mg once daily for up to 10 days in addition to standard care. Control intervention: Dexamethasone 6 mg once daily for up to 10 days in addition to standard care. Outcomes: The primary outcome is days alive without life support (i.e. mechanical ventilation, circulatory support, or renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions (i.e. anaphylactic reaction to hydrocortisone, new episode of septic shock, invasive fungal infection or clinically important gastrointestinal bleeding) at day 28; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, 90 and 180; and health-related quality of life at day 180. Sample size: A total of 1000 participants will be randomised in order to detect a 15% relative reduction in 28-day mortality combined with a 10% reduction in time on life support among the survivors with a power of 85%.

Official Title
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Higher vs. Lower Doses of Dexamethasone in Patients With COVID-19 and Severe Hypoxia

Conditions
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Covid19, Hypoxia

Intervention / Treatment
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* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All of the following must be fulfilled Aged 18 years or above AND Confirmed SARS-CoV-2 (COVID-19) requiring hospitalisation AND Use of one of the following: Invasive mechanical ventilation OR Non-invasive ventilation or continuous use of continuous positive airway pressure (CPAP) for hypoxia OR Oxygen supplementation with an oxygen flow of at least 10 L/min independent of delivery system Exclusion Criteria: We will exclude patients who fulfil any of the following criteria: Use of systemic corticosteroids for other indications than COVID-19 in doses higher than 6 mg dexamethasone equivalents Use of systemic corticosteroids for COVID-19 for 5 days consecutive days or more Invasive fungal infection Active tuberculosis Fertile woman (<60 years of age) with positive urine human gonadotropin (hCG) or plasma-hCG Known hypersensitivity to dexamethasone Previously randomised into the COVID STEROID 2 trial Informed consent not obtainable

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexamethasone 12 mg<br>Intravenous bolus injection of dexamethasone 12 mg once daily in addition to standard care for up to 10 days. We will allow the use of betamethasone 12 mg at sites, where dexamethasone is not available. | Drug: Dexamethasone<br>* ATC code: H02AB02<br>* Other names: Dexavit;|
| Active Comparator: Dexamethasone 6 mg<br>Intravenous bolus injection of dexamethasone 6 mg once daily in addition to standard care for up to 10 days. We will allow the use of betamethasone 6 mg at sites, where dexamethasone is not available. | Drug: Dexamethasone<br>* ATC code: H02AB02<br>* Other names: Dexavit;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days alive without life support at day 28 | Days alive without life support (i.e. invasive mechanical ventilation, circulatory support or renal replacement therapy) from randomisation to day 28 | Day 28 after randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with one or more serious adverse reactions | Serious adverse reactions defined as new episodes of septic shock, invasive fungal infection, clinically important gastrointestinal bleeding or anaphylactic reaction | Day 28 after randomisation | 
| All-cause mortality at day 28 | Death from all causes | Day 28 after randomisation | 
| All-cause mortality at day 90 | Death from all causes | Day 90 after randomisation | 
| Days alive without life support at day 90 | Days alive without life support (i.e. invasive mechanical ventilation, circulatory support or renal replacement therapy) from randomisation to day 90 | Day 90 after randomisation | 
| Days alive and out of hospital at day 90 | Number of days alive and out of hospital not limited to the index admission | Day 90 after randomisation | 
| All-cause mortality at day 180 | Death from all causes | Day 180 after randomisation | 
| Health-related quality of life at day 180 | Assessed by EQ-5D-5L | Day 180 after randomisation | 
| Health-related quality of life at day 180 | Assessed by EQ-VAS | Day 180 after randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomised clinical trial, COVID-19, Hypoxia, Corticosteroids