StEroids in hospitaLized patiEnts With Covid-19 in The Netherlands.

Study Overview
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Brief Summary
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Rationale: In patients with COVID-19 admitted to the hospital, large heterogeneity exists in patients, timing and dosing of steroid therapy. It is unclear how to treat patients who fail dexamethasone therapy. High-dose steroids are prescribed mainly in patients with the most severe disease, which may be too late given the potential escalation of pathophysiological pathways in these patients. Objectives: The main objective is to determine the most optimal form, timing and dosing of steroid therapy to reduce the morbidity and mortality of patients admitted to the hospital for COVID-19. This objective will be addressed in 4 work packages (WP): WP-1A-ward admission: What is the effect of higher dose steroids upon hospital admission on clinical deterioration and what would be the optimal timing of increasing steroid dosage? WP1B-ward late: Do high-dose steroids, compared to no steroids, improve outcomes in dexamethasone-unresponsive COVID-19 patients on the ward after dexamethasone 6 mg/day for 10 days? WP2-ICU admission: Do high-dose steroids, compared to 6 mg/day dexamethasone or its equivalent, improve outcomes in patients admitted to the ICU with moderate/severe C-ARDS? WP3-ICU late: Do high-dose steroids, compared to no steroids, improve outcomes in ICU patients with moderate/severe C-ARDS after dexamethasone 6 mg/day for 10 days? WP4-biobank: Can biomarkers help predict outcomes after (high dosed) steroid therapy? Study design: Retrospective observational multicenter study in the Netherlands. Study population: Adult patients (≥ 18 years) hospitalized with COVID-19 will be included, more specifically: Intervention (if applicable): Not applicable (retrospective study design). Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Given the retrospective nature of the study, no burden, risks or benefits for the patient are associated with participation. The target population of this study is specific to hospitalized patients with COVID-19.

Official Title
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Optimal Dosing and Timing of Corticosteroids in Hospitalized Patients With COVID-19.

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Steroids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for inclusion in any of the work packages, an individual must meet all of the following general inclusion criteria: Adult (i.e., ≥18 years) Hospitalized (i.e., admitted to the hospital) Laboratory-confirmed COVID-19 diagnosis (i.e., based on polymerase chain reaction-(PCR) test) WP1A- ward early: (1) Patients who present with WHO clinical progression scale class 4-5 (no oxygen therapy, Figure 5) when admitted to the ward with COVID-19. WP1B-ward late: Admitted to the ward (e.g., pulmonology ward, COVID-unit, etc.), excluding step-down units. In need of non-invasive oxygen therapy during hospital stay, including: Conventional oxygen therapy (COT) 1-5 L/min Conventional oxygen therapy (COT) 6-12 L/min Non-rebreather mask 12-15 L/min High-flow nasal cannula 16-60 L/min Non-invasive continuous positive airway pressure (CPAP) Non-invasive bilevel positive airway pressure (BiPAP) WP2-ICU admission/ WP3-ICU late: Admitted to the ICU>48 hours.* Invasive mechanical ventilation during ICU stay (intubation with endotracheal tube or tracheostomy) or extracorporeal membrane oxygenation (ECMO). ARDS according to the Berlin criteria WP4-biobank: The study population consists of patient subsets admitted to the ICU described in WP2 and WP3. Exclusion Criteria: General exclusion criteria: Mortality within 48 hours.* Opt-out (objection to participate) Criteria indicated with an asterisk (*) may or may not be applied, depending on data availability. These criteria will be instated if they result in excessive variation of the outcome or exposure, or result in difficulty in generalizing to the target population.

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Ward (e.g., pulmonology ward, COVID-unit, etc.),<br>WP1A: Patients with WHO clinical progression scale class 4-5 (i.e., no oxygen therapy) admitted to the ward with laboratory-confirmed COVID-19. WP1B: Adult patients admitted to the ward with laboratory-confirmed COVID-19 and on at least oxygen therapy. | Drug: Steroids<br>* Description of the intervention in each of the work packages: WP1A admission: Steroid dose >6mg/day dexamethasone equivalent will be compared to control (steroid = 6mg/day dexamethasone or equivalent steroid). WP1B late: After 10 days of dexamethasone therapy patients are stratified in high-dose steroids (> 6 mg dexamethasone or equivalent steroid) or no steroids up to day 28. WP2 ICU admission: High-dose steroids (dexamethasone >6 mg daily or equivalent corticosteroids) compared to dexamethasone 6 mg up to 72 hours after admission WP3 ICU late: After dexamethasone 6 mg for 10 days patients are stratified in high-dose steroids (dexamethasone >6 mg daily or equivalent corticosteroids) or no steroids up to day 28.<br>|
| Intensive Care Unit<br>Adult patients (≥18 years) admitted to the ICU with laboratory-confirmed COVID-19 and acute respiratory distress syndrome (ARDS) according to the Berlin definition criteria (i.e., receiving invasive mechanical ventilation). | Drug: Steroids<br>* Description of the intervention in each of the work packages: WP1A admission: Steroid dose >6mg/day dexamethasone equivalent will be compared to control (steroid = 6mg/day dexamethasone or equivalent steroid). WP1B late: After 10 days of dexamethasone therapy patients are stratified in high-dose steroids (> 6 mg dexamethasone or equivalent steroid) or no steroids up to day 28. WP2 ICU admission: High-dose steroids (dexamethasone >6 mg daily or equivalent corticosteroids) compared to dexamethasone 6 mg up to 72 hours after admission WP3 ICU late: After dexamethasone 6 mg for 10 days patients are stratified in high-dose steroids (dexamethasone >6 mg daily or equivalent corticosteroids) or no steroids up to day 28.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 28-day survival (WP2-3) | Alive at day 28 yes/no | Day 28 | 
| 28-day need of invasive mechanical ventilation (WP2-3) | Need for mechanical ventilation at day 28 yes/no | Day 28 | 
| Need for WHO severity 6-9 (WP1) | WHO clinical progression scale class 6: high flow nasal cannula WHO class 7-9: invasive ventilation | From date of hospital admission up to date of hospital discharge, assessed up to 12 months | 
| Hospital mortality in patients who receive HFNC or invasive mechanical ventilation due to restrictions in care (WP1) | Restrictions in care (either on medical grounds or by advance directive of the patient) | From date of hospital admission up to date of hospital discharge, assessed up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ICU mortality | Death at ICU including date | During ICU stay | 
| Hospital mortality | In-hospital death including date | From date of hospital admission up to date of hospital discharge, assessed up to 12 months | 
| Hospital length of stay | The number of days from the date of hospital admission to date of hospital discharge or death | From date of hospital admission up to date of hospital discharge, assessed up to 12 months | 
| ICU length of stay | The number of days from the date of ICU admission to date of ICU discharge or death | During ICU stay | 
| Mechanical ventilation duration | Total duration of mechanical ventilation in days | During ICU stay | 
| Ventilator free days and alive | Number of ventilator free days at day 28 | Day 28 | 
| Rate of respiratory and inflammatory complications during hospital stay | Aspergillus, Herpes simplex virus (HSV),Cytomegalovirus (CMV), Ventilator-associated pneumonia (VAP), Catheter-related bloodstream infection (CRBSI) | From date of hospital admission up to date of hospital discharge, assessed up to 12 months | 
| Rate of general systemic complications during hospital stay | Myocardial infarction, deep venous thrombosis, pulmonary embolus, hyperglycemia, hypoglycemia, acute kidney injury, delirium, sepsis | From date of hospital admission up to date of hospital discharge, assessed up to 12 months |