StEroids in hospitaLized patiEnts With Covid-19 in The Netherlands. (SELECT)

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

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.

Study Overview

• Status: Recruiting
• Conditions: COVID-19
• Intervention / Treatment: Drug: Steroids

• Study Type: Observational
• Enrollment (Estimated): 3800

Contacts and Locations

• Study Contact: Name: Jilske Huijben, MD, PhD; Phone Number: +31 (010) 703 98 83; Email: j.a.huijben@erasmusmc.nl

Study Locations

• Netherlands
  • Rotterdam, Netherlands
    • Recruiting
    • Erasmus MC
    • Contact: Jilske Huijben; Email: j.a.huijben@erasmusmc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Adult patients (≥18 years) hospitalized with laboratory-confirmed COVID-19.The (hospitalized) study population is expected to consist mainly of older, male, obese patients who suffer from comorbidities, like hypertension, diabetes mellitus. Around 40% of these patients require invasive mechanical ventilation. The investigators will include patients from all SARS-CoV-2 epidemic waves (including the first wave).

Description

Inclusion Criteria:

To be eligible for inclusion in any of the work packages, an individual must meet all of the following general inclusion criteria:

1. Adult (i.e., ≥18 years)
2. Hospitalized (i.e., admitted to the hospital)
3. 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:

1. Admitted to the ward (e.g., pulmonology ward, COVID-unit, etc.), excluding step-down units.

2. 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:

1. Admitted to the ICU>48 hours.*
2. Invasive mechanical ventilation during ICU stay (intubation with endotracheal tube or tracheostomy) or extracorporeal membrane oxygenation (ECMO).
3. 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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Ward (e.g., pulmonology ward, COVID-unit, etc.),; 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; 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.
Intensive Care Unit; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Henrik Endeman
• Collaborators: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); St. Antonius Hospital; Maasstad Hospital; Academisch Ziekenhuis Groningen; OLVG; Isala; Amphia Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2022
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: June 1, 2022
• First Submitted That Met QC Criteria: June 2, 2022
• First Posted (Actual): June 3, 2022

Study Record Updates

• Last Update Posted (Estimated): December 1, 2023
• Last Update Submitted That Met QC Criteria: November 30, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: 10430102110010

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be made available through a secure data transfer system and appropriate data transfer agreement. (The data set contains personal data.)
• IPD Sharing Access Criteria: Reasonable requests via email (including a protocol describing the research question and data needed) are considered.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No