Effect of Two Different Doses of Dexamethasone in Patients With ARDS and COVID-19 (REMED)

March 20, 2023 updated by: Jan Malaska, Brno University Hospital

Effect of Dexamethasone in Patients With ARDS and COVID-19 - Prospective, Multi-centre, Open-label, Parallel-group, Randomized Controlled Trial (REMED Trial)

REMED is a prospective, phase II, open-label, randomised controlled trial testing superiority of dexamethasone 20 mg vs 6 mg. The trial aims to be pragmatic, i.e. designed to evaluate the effectiveness of the intervention in conditions that are close to real-life routine clinical practice. The study is multi-centre and will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic. This is an open-label trial in which the participants and the study staff will be aware of the allocated intervention. Blinded pre-planned statistical analysis will be performed.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Since December 2019, Covid-19 virus has infected millions of people worldwide. A significant number of patients develop hyperinflammatory state affecting lungs, which may lead to the need of oxygen therapy. In most severe cases, acute respiratory distress syndrome (ARDS) develops and high flow oxygen therapy or invasive mechanical ventilation is necessary (Wu et al., 2020). Therapeutic options in Covid-19 associated ARDS patients remain limited and mortality is still excessive. Systemic corticosteroids have potential to limit hyperinflammatory response by modulating immune system. This effect is mediated mainly by binding to glucocorticosteroid receptor α (GRα)(Meduri et al., 2020). Their effectiveness was proved in heterogeneous ARDS patients recently (Villar et al., 2020). In patients with Covid-19 pneumonia in need for oxygen therapy or mechanical ventilation, dexamethasone 6 mg per day is currently recommended. This therapy is mandated by the results of RECOVERY trial (Horby et al., 2020). After this trial was published, three randomised trials comparing hydrocortisone (Angus et al., 2020; Dequin et al., 2020) or dexamethasone (Tomazini et al., 2020) against placebo were stopped prematurely. All these studies were included in the subsequent IPD metaanalysis (Sterne et al., 2020). However, dose of 6 mg of dexamethasone is currently being reappraised. The aforementioned study in non Covid-19 ARDS patients (Villar et al., 2020) used 20 mg of dexamethasone per day, which is roughly equivalent to the methylprednisolone regimen (1mg/kg/day) studied in early severe ARDS patients (Meduri et al., 2007). Only these moderate doses (80-100 mg of methylprednisolone, equivalent to 15-19 mg of dexamethasone) have full potential to modulate immune response by saturating GRα receptors (Meduri et al., 2020). Importantly, prematurely stopped CoDEX trial (Tomazini et al., 2020) comparing dexamethasone against placebo in Covid-ARDS patients, used initial daily dose of 20 mg of dexamethasone versus placebo.

In the light of these facts, 6 mg of dexamethasone given to COVID-19 patients with different severity of illness (WHO classification group 5-10) may miss important therapeutic potential or may prevent a potential deleterious effects of a full dose therapeutic corticosteroid. Authors hypothesize that the patients with moderate to severe ARDS undergoing mechanical ventilation may benefit from higher doses of dexamethasone (Villar et al., 2020; Tomazini et al., 2020; Meduri et al., 2007).

The primary objective of this study is to test the hypothesis that administration of dexamethasone 20 mg is superior over 6 mg in adult patients with moderate or severe ARDS due to confirmed COVID-19.

Primary endpoint: Number of ventilator-free days (VFDs) at 28 days after randomisation, defined as being alive and free from mechanical ventilation (more than 48 hours).

Secondary endpoints:

  1. Mortality from any cause at 60 days after randomization;
  2. Dynamics of inflammatory marker (CRP) change from Day 1 to Day 14;
  3. WHO Clinical Progression Scale at Day 14 (range 0-10; 0 = no illness, 1-9 = increasing level of care, and 10 = death);
  4. Adverse events related to corticosteroids (new infections, new thrombotic complications) until Day 28 or hospital discharge;
  5. Independence at 90 days after randomization assessed by Barthel Index The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days through telephone structured interview using Barthel Index.

Study Type

Interventional

Enrollment (Actual)

235

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Czechia
      • Brno, Czechia, 62500
        • University Hospital Brno

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion criteria:

Subjects will be eligible for the trial if they meet all of the following criteria:

  1. Adult (≥ 18 years of age) at time of enrolment;
  2. Present COVID-19 (infection confirmed by RT-PCR or antigen testing);
  3. Intubation/mechanical ventilation or ongoing high-flow nasal cannula (HFNC) oxygen therapy;

  4. Moderate or severe ARDS according to Berlin criteria:

    • Moderate - PaO2/FiO2 100-200 mmHg;
    • Severe - PaO2/FiO2 < 100 mmHg;
  5. Admission to ICU in the last 24 hours.

Exclusion criteria:

Subjects will not be eligible for the trial if they meet any of the following criteria:

  1. Known allergy/hypersensitivity to dexamethasone or excipients of the investigational medicinal product (e.g. parabens, benzyl alcohol);
  2. Fulfilled criteria for ARDS for ≥ 14 days at enrolment;
  3. Pregnancy or breastfeeding;
  4. Unwillingness to comply with contraception measurements from the enrolment to at least 1 week after the last dose of dexamethasone (sexual abstinence is considered as the adequate contraception method);
  5. End-of-life decision or patient is expected to die within next 24 hours;
  6. Decision not to intubate or ceilings of treatment in place;

  7. Immunosuppression and/or immunosuppressive drugs in medical history:

    1. Systemic immunosuppressive drugs or chemotherapy in the past 30 days;
    2. Systemic corticosteroids use before hospitalization;
    3. Any dose of dexamethasone during the present hospital stay for COVID-19 for more than (≥) last 5 days before enrolment;
    4. Systemic corticosteroids during present hospital stay for other conditions than COVID-19 (e.g. septic shock);
  8. Present haematological or generalized solid malignancy;

  9. Any of contraindications of corticosteroids, e.g.

    • intractable hyperglycaemia;
    • active gastrointestinal bleeding;
    • adrenal gland disorders;
    • a presence of superinfection diagnosed with locally established clinical and laboratory criteria without adequate antimicrobial treatment;
  10. Cardiac arrest before ICU admission;
  11. Participation in another interventional trial in the last 30 days.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: DEX 20 mg
Patients in the intervention group after randomization will receive dexamethasone 20 mg intravenously once daily on day 1-5, followed by dexamethasone 10 mg intravenously once daily on day 6-10.
Drug: Dexamethasone
Patients in the intervention group after randomization will receive dexamethasone 20 mg intravenously once daily on day 1-5, followed by dexamethasone 10 mg intravenously once daily on day 6-10. If successful extubation occurs before day 10, treatment with dexamethasone is withdrawn.
Active Comparator: DEX 6 mg
Patients in the control group after randomization will receive dexamethasone 6 mg day 1-10.
Drug: Dexamethasone
Patients in the intervention group after randomization will receive dexamethasone 20 mg intravenously once daily on day 1-5, followed by dexamethasone 10 mg intravenously once daily on day 6-10. If successful extubation occurs before day 10, treatment with dexamethasone is withdrawn.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of ventilator-free days (VFDs) at 28 days after randomization
Time Frame: 28 days
Number of ventilator-free days (VFDs) at 28 days after randomisation, defined as being alive and free from mechanical ventilation (more than 48 hours)
28 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mortality from any cause at 60 days after randomization
Time Frame: 60 days
60 days
WHO clinical progression scale at day 14
Time Frame: 14 days
WHO clinical progression scale (range, 0-10, where 0 = no illness, 1-9 = increasing level of care, and 10 = death) (WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection, 2020) assessed at day 14
14 days
Dynamics of inflammatory marker
Time Frame: 14 days
Dynamics of inflammatory marker (CRP) change from Day 1 to Day 14
14 days
Adverse events related to corticosteroids
Time Frame: 28 days
new infections, new thrombotic complications
28 days
Functional independence
Time Frame: 90 days
Independence at 90 days after randomization assessed by Barthel Index
90 days

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Long-term outcome regarding mortality
Time Frame: 180 and 360 days
Death from any cause at 180 and 360 days
180 and 360 days
Long-term outcome regarding functional independence
Time Frame: 180 and 360 days
Functional independence at 180 and 360 days assesed through telephone structured interview using Barthel Index.
180 and 360 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Brno University Hospital

Collaborators

University Hospital Ostrava
University Hospital Olomouc
Vascular surgery, University hospital Královské Vinohrady, Prague
Masaryk University
General University Hospital in Prague
St. Anne's University Hospital Brno
University Hospital Motol Prague
University Hospital Plzeň
Tomáš Baťa Regional Hospital
Military University Hospital Praha

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 2, 2021

Primary Completion (Actual)

March 9, 2022

Study Completion (Actual)

February 23, 2023

Study Registration Dates

First Submitted

December 9, 2020

First Submitted That Met QC Criteria

December 10, 2020

First Posted (Actual)

December 11, 2020

Study Record Updates

Last Update Posted (Actual)

March 22, 2023

Last Update Submitted That Met QC Criteria

March 20, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CZECRIN No. 2020/47
  • 2020-005887-70 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Collected data will be shared with other ongoing clinical trials on the same topic for individual patient ́s data (IPD) metaanalysis or shared upon relevant requests. Also de-identified participant-level dataset will be made available 6 months after the publication of the results of the study at www.mendeley.com

IPD Sharing Time Frame

De-identified participant-level dataset will be made available 6 months after the publication of the results of the study at www.mendeley.com

IPD Sharing Access Criteria

Planned IPD metaanalysis or other relevant request

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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