Clinical trial NCT04663555: Effect of Two Different Doses of Dexamethasone in Patients With ARDS and COVID-19
Official title: Effect of Dexamethasone in Patients With ARDS and COVID-19 - Prospective, Multi-centre, Open-label, Parallel-group, Randomized Controlled Trial (REMED Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Covid19
ARDS
Keywords: Covid19
ARDS
dexamethasone
Lead sponsor: Brno University Hospital
Sponsor class: OTHER
Collaborators: name: Masaryk University
name: Vascular surgery, University hospital Královské Vinohrady, Prague
name: General University Hospital, Prague
name: University Hospital Ostrava
name: St. Anne's University Hospital Brno
name: Motol University Hospital
name: University Hospital Olomouc
name: University Hospital Plzeň
name: Tomáš Baťa Regional Hospital
name: Military University Hospital Praha
First posted: 2020-12-11
Enrollment: 235
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: REMED is a prospective phase II open-label randomized controlled trial testing superiority of dexamethasone 20 mg vs 6 mg. The study is multi-centre and will be conducted in intensive care units (ICUs) of university hospitals in the Czech Republic. The trial aims to be pragmatic, i.e. designed to evaluate the effectiveness of the intervention in conditions that are very close to the real-life routine clinical practice. Dexamethasone will be administered once daily intravenously for 10 days. 300 participants will be enrolled and followed up for 360 days after randomization.

Following stratification factors will be applied:

* Age \< 65 and ≥ 65 (12);
* Charlson Comorbidity index (CCI; APPENDIX B Assessment tools, scores, and scales, Chapter 14.2) \< 3 and ≥ 3;
* CRP \< 150 mg/L and ≥ 150 mg/L
* Trial centre. Patients will be randomized in 1 : 1 ratio in one of the two treatment arms. Randomization through eCRF will be available 24 hours every day.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of ventilator-free days (VFDs) at 28 days after randomization
timeFrame: 28 days
Secondary outcomes:
measure: Mortality from any cause at 60 days after randomization
timeFrame: 60 days
measure: WHO clinical progression scale at day 14
timeFrame: 14 days
measure: Dynamics of inflammatory marker
timeFrame: 14 days
measure: Adverse events related to corticosteroids
timeFrame: 28 days
measure: Functional independence
timeFrame: 90 days
Other outcomes:
measure: Long-term outcome regarding mortality
timeFrame: 180 and 360 days
measure: Long-term outcome regarding functional independence
timeFrame: 180 and 360 days
Locations:
city: Brno
country: Czechia
facility: University Hospital Brno
Study officials:
References:
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