Effect of Dexamethasone in Patients With ARDS and COVID-19 - Prospective, Multi-centre, Open-label, Parallel-group, Randomized Controlled Trial (REMED Trial)
Phase: PHASE4
Conditions: Covid19, ARDS
Sponsor: Brno University Hospital

 
 
 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
Study Title: 
Effect of dexamethasone in patients with ARDS and COVID-19 – 
prospective, multi-centre, open-label, parallel-group, randomized 
controlled trial (REMED trial) 
 
 
Short title: 
Effect of two different doses of dexamethasone in patients 
with ARDS and COVID-19 
Protocol code: 
 
 
REMED 
 
EudraCT No.: 
 
 
2020-005887-70 
ClinicalTrials.gov Identifier:  
NCT04663555 
Version | Date:  
 
 
1.1 | 15.01.2021 
 
Sponsor: 
 
 
 
Fakultní nemocnice Brno 
Jihlavská 20 
625 00 Brno, Czech Republic 
 
This trial protocol contains strictly confidential information and is intended solely for the 
guidance of the clinical investigation. This protocol may not be disclosed to parties not 
associated with the clinical research or used for any purpose without the prior written consent 
of the investigator. 
 
 

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STATEMENT 
The following persons undertake to conduct the study "Effect of dexamethasone in patients 
with ARDS and COVID-19 – prospective, multi-centre, open-label, parallel-group, 
randomized controlled trial (REMED trial)" according to this protocol and in compliance with 
applicable national and international requirements, mainly: 
• 
Declaration of Helsinki, as amended in 2013;  
• 
Good Clinical Practice according to International Conference on Harmonisation, as 
amended by ICH E6(R2);  
• 
Act No. 378/2007 Coll., on Pharmaceuticals, as amended; 
• 
Decree No. 226/2008 Coll., on Good clinical practice and detailed conditions of clinical 
trials on medicinal products, as amended;  
• 
Act No. 18/2018 Coll., on Personal data protection. 
 
 
 
 
 
Signature 
Date 
Person responsible 
for the clinical trial 
on sponsor's side  
 
 
 
Investigator 
responsible for the 
clinical trial and 
address of the centre 
 
 
 
 
 
 

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LIST OF TRIAL CENTRES AND PRINCIPLE INVESTIGATORS 
Coordinating centre 
Department of Anaesthesiology and Intensive Care Medicine 
University Hospital Brno 
Jihlavská 20, 625 00 Brno, Czech Republic 
 
University Hospital Brno 
Jihlavská 20 
625 00 Brno, Czech Republic 
 
 
 
University Hospital Královské Vinohrady 
Šrobárova 1150 
100 34 Praha, Czech Republic  
 
 
General University Hospital in Prague  
U Nemocnice 499/2 
128 08 Praha, Czech Republic  
 
University Hospital Ostrava 
17. listopadu 1790 
708 52 Ostrava-Poruba, Czech Republic 
 
St. Anne’s University Hospital 
Pekařská 664/53 
656 91 Brno, Czech Republic 
 
 
University Hospital Motol 
V Úvalu 84/1 
150 06 Praha 5, Czech Republic 
 
 
University Hospital Olomouc 
I. P. Pavlova 185/6 
779 00 Olomouc, Czech Republic 
 
 
University Hospital Plzeň 
alej Svobody 80 
304 60 Plzeň-Lochotín, Czech Republic  
 
Tomáš Baťa Regional Hospital 
Havlíčkovo nábřeží 600 
762 75 Zlín, Czech Republic 
 
 
 
Military University Hospital Praha 
U Vojenské nemocnice 1200 
169 02 Praha, Czech Republic
 
 
 
 

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CONTENTS 
STATEMENT ........................................................................................................................................... 2 
LIST OF TRIAL CENTRES AND PRINCIPLE INVESTIGATORS .......................................................... 3 
CONTENTS ............................................................................................................................................. 4 
LIST OF ABBREVIATIONS .................................................................................................................... 6 
1. 
CLINICAL TRIAL BACKGROUND .............................................................................................. 7 
 
Introduction .......................................................................................................................... 7 
 
Rationale and up-to-date evidence ...................................................................................... 7 
 
Anticipated risks and benefits .............................................................................................. 7 
2. 
TRIAL OBJECTIVES AND ENDPOINTS .................................................................................... 8 
 
Primary objective(s) and endpoint(s) ................................................................................... 8 
 
Secondary objective(s) and endpoint(s) .............................................................................. 8 
 
Exploratory objective(s) and endpoint(s) ............................................................................. 8 
3. 
TRIAL DESIGN ............................................................................................................................ 8 
4. 
TRIAL POPULATION .................................................................................................................. 9 
 
Inclusion criteria ................................................................................................................... 9 
 
Exclusion criteria.................................................................................................................. 9 
 
Randomization and stratification ....................................................................................... 10 
 
Blinding .............................................................................................................................. 10 
 
Enrolment stopping rules ................................................................................................... 10 
 
Premature termination of participation in the trial .............................................................. 10 
5. 
STUDY TREATMENT ............................................................................................................... 11 
 
Dexamethasone (ATC code: H02AB02) ............................................................................ 11 
5.1.1. 
Qualitative and quantitative composition ................................................................... 11 
5.1.2. 
Pharmaceutical form and route of administration ...................................................... 11 
5.1.3. 
Other information ....................................................................................................... 11 
 
Packaging and labelling ..................................................................................................... 12 
 
Delivery and storage .......................................................................................................... 12 
 
Dosing schedule ................................................................................................................ 12 
 
Dose modification and delays ............................................................................................ 12 
 
Permitted concomitant medication .................................................................................... 12 
 
Restricted concomitant medication .................................................................................... 13 
6. 
COURSE OF THE TRIAL .......................................................................................................... 13 
 
Screening of eligible patients ............................................................................................. 13 
 
Overview of medical care about the study participant ....................................................... 13 
 
Clinical examinations and assessments ............................................................................ 14 
 
Study procedures .............................................................................................................. 16 
 
Biological samples ............................................................................................................. 17 
 
Assessment tools, scores and scales ................................................................................ 17 
7. 
SAFETY ASSESSMENTS ......................................................................................................... 17 
 
Definitions (according to the Directive 2001/20/EG) .......................................................... 17 
 
AE surveillance, recording and documentation ................................................................. 18 
 
Treatment of AE ................................................................................................................ 19 
 
Assessment of seriousness ............................................................................................... 19 
 
Assessment of intensity (severity) ..................................................................................... 19 
 
Assessments of causality .................................................................................................. 19 
 
Reporting of SAE and SUSAR .......................................................................................... 20 
 
Pregnancy ......................................................................................................................... 21 

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8. 
STATISTICS .............................................................................................................................. 21 
 
Sample size determination ................................................................................................ 21 
 
Analysis of efficacy ............................................................................................................ 22 
8.2.1. 
Subgroup analysis ..................................................................................................... 22 
 
Analysis of safety ............................................................................................................... 22 
 
Planned interim analysis .................................................................................................... 22 
 
Missing data ...................................................................................................................... 22 
9. 
DATA MANAGEMENT AND QUALITY ASSURANCE .............................................................. 23 
 
eCRF database ................................................................................................................. 23 
 
Trial documents, medical records ...................................................................................... 23 
 
Monitoring and auditing ..................................................................................................... 23 
 
Steering committee ............................................................................................................ 23 
 
Data monitoring committee ................................................................................................ 23 
10. 
ETHICAL ASPECTS .............................................................................................................. 24 
 
Informed consent procedure .............................................................................................. 24 
10.1.1. 
Fully conscious and oriented patients ........................................................................ 24 
10.1.2. 
Patients lacking the capacity to decide ...................................................................... 24 
 
Supervision of the informed consent procedure ................................................................ 25 
 
Vulnerable population ........................................................................................................ 25 
11. 
PUBLICATION POLICY ........................................................................................................ 25 
12. 
FINANCING AND INSURANCE ............................................................................................ 25 
14. 
SUPPLEMENTS/APPENDICES ............................................................................................ 28 
 
APPENDIX A Specimen of labelling .................................................................................. 28 
 
APPENDIX B Assessment tools, scores and scales ......................................................... 28 
14.2.1. 
APACHE II ................................................................................................................. 28 
14.2.2. 
Barthel index .............................................................................................................. 28 
14.2.3. 
Charlson comorbidity index ....................................................................................... 28 
14.2.4. 
COV-HI ...................................................................................................................... 29 
14.2.5. 
Glasgow coma scale .................................................................................................. 29 
14.2.6. 
Spontaneous breathing trial ....................................................................................... 29 
14.2.7. 
WHO Clinical Progression Scale ............................................................................... 29 
 

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LIST OF ABBREVIATIONS 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
CCI 
Charlson Comorbidity Index 
CDK 
Chronic kidney disease 
COV-HI 
COVID-19-associated hyperinflammation 
CPS 
Clinical Progression Scale 
CRF, eCRF 
(electronic) Case Report Form 
CRP 
C-reactive protein 
CYP 
Cytochrome 
ECMO 
Extracorporeal membrane oxygenation 
EVCTM 
EudraVigilance Clinical Trials Module 
FiO2 
Inspiratory fraction of oxygen 
GCP 
Good Clinical Practice 
GR 
Glucocorticoid receptor 
hCG 
Human chorionic gonadotropin 
HFNC 
High Flow Nasal Cannula 
ICH 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
ICU 
Intensive Care Unit 
IPD 
Individual patients' data 
ITT 
Intention to treat 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
PEEP 
Positive end-expiratory pressure 
PP 
Per protocol 
Ppl 
Plateau pressure 
RBC 
Red blood cells 
RR 
Respiratory rate 
RT-PCR 
Polymerase chain reaction with reverse transcription  
SADR 
Serious adverse reaction 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome-related Coronavirus 2 
SBT 
Spontaenous breathing trial 
SD 
Standard deviation 
SmPC 
Summary of product characteristics 
SpO2 
Oxygen saturation 
SUSAR 
Suspected unexpected serious adverse reaction 
UADR 
Unexpected adverse reaction 
VAP/HAP 
Ventilator-associated pneumonia/Hospital-acquired pneumonia 
VFD 
Ventilator-free day 
WBC 
White blood cells 
WHO 
World Health Organization 
 
 
 

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1. CLINICAL TRIAL BACKGROUND 
 Introduction 
Since December 2019, SARS-Co-2 virus has infected millions of people worldwide. A 
significant number of patients develop hyperinflammatory state affecting lungs, which may lead 
to the need for oxygen therapy. In most severe cases, acute respiratory distress syndrome 
(ARDS) develops and high flow oxygen therapy or invasive mechanical ventilation is necessary 
(1). Therapeutic options in coronavirus disease 2019 (COVID-19) associated ARDS patients 
remain limited and mortality is still excessive.  
 Rationale and up-to-date evidence 
Systemic corticosteroids have the potential to limit hyperinflammatory response by modulating 
the immune system. This effect is mediated mainly by binding to the glucocorticoid receptor 
(GR) α (2). Their effectiveness was proved in heterogeneous ARDS patients recently (3). 
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 (4). After this trial was published, three randomized trials comparing 
hydrocortisone (5,6) or dexamethasone (7) against placebo were stopped prematurely. All 
these studies were included in the subsequent individual patients' data (IPD) meta-analysis 
(8). However, the dose of 6 mg of dexamethasone is currently being reappraised.  
The aforementioned study in non-COVID-19 ARDS patients (3) used 20 mg of dexamethasone 
per day, which is roughly equivalent to the methylprednisolone regimen (1 mg/kg/day) studied 
in early severe ARDS patients (9). Only these moderate doses (80–100 mg of 
methylprednisolone, equivalent to 15–19 mg of dexamethasone) have the full potential to 
modulate the immune response by saturating GRα receptors (2). Importantly, prematurely 
stopped CoDEX trial (7) comparing dexamethasone against placebo in COVID-19 ARDS 
patients used an 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 (3,7,9). 
 Anticipated risks and benefits 
There may or may not benefit from a higher dose of dexamethasone in the improvement of the 
clinical outcomes of an individual participant. However, there is a potential benefit to society 
from the participation in this study resulting from insights gained about the dexamethasone 
use and posology. The potential risks of participating in this study are those associated with 
dexamethasone use, i.e. known adverse effects of potent glucocorticoids. 
 
 

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2. TRIAL OBJECTIVES AND ENDPOINTS 
 Primary objective(s) and endpoint(s) 
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 randomization. 
VFDs were defined according to recent recommendations (10): 
• 
Day 0 is the day of randomization 
• 
Time frame is 28 days 
• 
Successful extubation means extubation for > 48 h without reintubation in a 28-d survivor 
• 
Interval reintubations – VFDs are counted from last successful extubation 
• 
If death occurs before Day 28, VFD = 0 (to penalize non-survival, regardless of intubation 
status)  
• 
If death occurs after Day 28, 28-d ventilation and survival status is used for calculating 
VFDs (censor after 28 days) 
 Secondary objective(s) and endpoint(s) 
The secondary objective is to investigate the efficacy and safety of dexamethasone 20 mg 
versus dexamethasone 6 mg. 
Secondary endpoints: 
a) Mortality from any cause at 60 days after randomization;  
b) Dynamics of inflammatory marker (CRP) change from Day 1 to Day 14; 
c) WHO Clinical Progression Scale at Day 14 (range 0–10; 0 = no illness, 1–9 = increasing 
level of care, and 10 = death; APPENDIX B 
Assessment tools, scores, and scales, 
Chapter 14.2) (11); 
d) Adverse events related to corticosteroids (new infections, new thrombotic complications) 
until Day 28 or hospital discharge;  
e) Independence at 90 days after randomization assessed by Barthel Index (APPENDIX B
 
Assessment tools, scores, and scales, Chapter 14.2). 
 Exploratory objective(s) and endpoint(s) 
The exploratory objective of this study is to assess long-term consequences on mortality 
and quality of life at 180 and 360 days. 
3. TRIAL DESIGN 
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 

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intravenously for 10 days. 300 participants will be enrolled and followed up for 360 days after 
randomization.  
4. TRIAL POPULATION 
 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: 
a) Systemic immunosuppressive drugs or chemotherapy in the past 30 days; 
b) Systemic corticosteroids use before hospitalization; 
c) Any dose of dexamethasone during the present hospital stay for COVID-19 for more 
than (≥) last 5 days before enrolment; 
d) 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. 
 

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 Randomization and stratification 
Randomization will be carried out within the electronic case report form (eCRF) by the stratified 
permuted block randomization method. The allocation sequences will be prepared by a 
statistician independent of the study team. Allocation to the treatment arm of an individual 
patient will not be available to the investigators before the completion of the whole 
randomization process. 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. 
 Blinding 
This is an open-label trial, in which the participants and the study staff will learn about the 
allocated intervention. Blinded pre-planned statistical analysis will be performed (13) according 
to Chapter 8. 
 Enrolment stopping rules 
Enrolment of new subjects into the trial will be stopped if any of the following is encountered 
until the sponsor determines if it is safe for the trial to continue enrolment: 
• 
Death that is related to dexamethasone; 
• 
SAE or SUSAR (see Chapter 7.7) that is related to dexamethasone during 28 days post-
administration; 
• 
Emergence of new data that may lead to the trial becoming unethical. This may be merely 
due to safety concerns of the interventional group (e.g., if harm is reported by other trials).  
• 
After the interim analysis, the Steering committee will review primary outcomes and the 
summary of adverse events in both arms whilst still blinded to treatment allocation. The 
enrolment can be stopped if the following criteria are fulfilled:  
a) There is a significant difference in the primary outcome at p < 0.01 between the 
arms. 
b) Futility: The futility criterion is not binding for the Steering committee. Based on 
available data, the study statistician calculates the probability of being able to reject 
the null hypothesis with achieving the target number of subjects and the probability 
of type II error made by stopping the trial prematurely. 
 Premature termination of participation in the trial 
Reasons for early termination of a patient's participation include: 
• 
Withdrawal of informed consent (subject's decision to withdraw for any reason); 
• 
Important deviation in the process of informed consent (Chapter 10.1); 
• 
Life-threatening adverse reaction to dexamethasone at the discretion of the 
investigator; 

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• 
Newly-emerged pregnancy of a participant after the enrolment; 
Subjects can terminate their participation prematurely at any time at their request for any 
reason, but they must notify the investigator. The investigator must contact the sponsor to 
report the premature discontinuation. 
The investigator must: 
• 
Instruct the participant about the right on early termination of participation; 
• 
Assure him/her that the end of participation will not affect the attitude of the physician, 
or further treatment and its quality; 
• 
Ask for discussing this decision with the investigator in advance; 
• 
Make a note in the patient's medical records and eCRF about the date of early 
termination of participation. 
The sponsor reserves the right to discontinue the study at any time if there is a significant 
safety concern (e.g. grade 4 adverse reactions to dexamethasone), or insufficient recruitment 
despite intensified efforts to enrol patients, or if repeated poor study documentation occurs at 
a site. The trial can be discontinued by the decision of the regulatory authority or ethics 
committee, as well. 
5. STUDY TREATMENT  
 Dexamethasone (ATC code: H02AB02) 
Dexamethasone solution for injection/infusion is the investigational medicinal product as well 
as the comparator. The trial will assess two doses, 20 mg (investigational) vs 6 mg 
(comparator). 
All authorized medicinal products containing dexamethasone  
in the form of solution for i.v. injection/infusion can be used. 
 
5.1.1. Qualitative and quantitative composition 
Active pharmaceutical ingredient: Dexamethasone sodium phosphate (4 mg/mL) 
Excipients: Excipients differ in various dexamethasone solutions for inj./inf. Please see the 
SmPC of the medicinal product you are using. Several excipients have known biological effects 
(e.g., allergic reactions): methylparaben, propylparaben, benzyl alcohol. Allergy or 
hypersensitivity to dexamethasone or excipients is an exclusion criterion (Chapter 4.2). 
5.1.2. Pharmaceutical form and route of administration 
Solution for injection/infusion; intravenous administration 
5.1.3. Other information 
Detailed pharmacological profile of the drug, including information on the mechanism of action, 
contraindications, drug interactions, adverse effects and others can be found in the SmPC. 
 

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 Packaging and labelling 
The medicinal product will be labelled in accordance with applicable legislation. Specimen of 
the labelling can be found in APPENDIX A, Chapter 14.1. 
 Delivery and storage 
The medicinal product containing dexamethasone will be ordered regularly by trial sites' 
hospital pharmacies and taken from the Czech market. It will be stored up to 30°C in the 
secondary package to keep it from the light according to the SmPC recommendations. 
 Dosing schedule 
Patients in the intervention group will receive dexamethasone 20 mg intravenously once daily 
on day 1–5, followed by dexamethasone 10 mg intravenously once daily on day 6–10. 
Patients in the control group will receive dexamethasone 6 mg day 1–10. 
 Dose modification and delays 
For this study, no dose modification or delays are possible. 
Previous treatment with any dose of dexamethasone for more than (≥) 5 days during the 
present hospital stay for COVID-19 is an exclusion criterion (Chapter 4.2, point 6c). If the study 
subject is treated with any dose of dexamethasone for less than 5 days before the enrolment, 
he/she can be enrolled, and there will be no changes in the duration of study drug 
administration.  
 Permitted concomitant medication 
Study participants will receive the best standard of care according to local protocols and 
national guidelines, including the state-of-the-art anti-infective and adjunctive treatment of 
COVID-19, sedation and delirium management, physiotherapy, ventilator, and haemodynamic 
management. 
Currently, the standard of care for hospitalized patients with COVID-19 that require oxygen 
support (14) can consist of:  
• 
remdesivir (at the discretion of the investigator); 
• 
prevention of thromboembolic disease (anticoagulants); 
• 
gastric ulcer prophylaxis for patients on dexamethasone; 
• 
nutrition, hydration, electrolytes, vitamins, and glucose administration; 
• 
antipyretics (paracetamol, metamizole); 
• 
antibiotics; 
• 
bronchodilators. 
All chronic medication prescribed to the patient before the enrolment is permitted to continue 
with the exceptions defined in Chapter 4.2 (point 6) and Chapter 5.7. All necessary 
medication needed during the trial is allowed with exceptions defined in Chapter 5.7.  
 
 

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 Restricted concomitant medication 
Systemic corticosteroids other than dexamethasone are restricted, as well as other 
investigational medicinal products currently tested for the treatment of COVID-19 (e.g., 
investigational antivirals, or monoclonal antibodies). Remdesivir is not considered as an 
investigational drug, as it has already been authorized. 
Concomitant treatment with potent inhibitors of CYP3A increases the risk of systemic 
adverse effects of dexamethasone. In cases where benefits of such treatment do not 
overweight this increased risk, combination with strong inhibitors of CYP3A is considered 
restricted. 
Potent inhibitors of CYP3A include e.g., systemic azole antimycotics, clarithromycin, 
erythromycin, telithromycin, diltiazem, and verapamil. 
Concomitant use of potent inducers of CYP3A decreases the effect of dexamethasone, 
which may then bias the results. In cases where benefits of such treatment do not overweight 
this risk of bias, combination with potent inducers of CYP3A is considered restricted. 
Potent inducers of CYP3A include e.g., phenytoin, rifampicin, phenobarbital, and 
carbamazepine. 
Detailed information on drug interactions could be found in SmPC. 
6. COURSE OF THE TRIAL 
 Screening of eligible patients 
Patients admitted to ICU of each centre will be screened daily for the eligibility, and all the 
patients will be recorded in the screening log of eCRF. For patients with the completion of 
consent, appropriate enrolment information will be recorded to eCRF and only after all required 
information are provided the randomization and allocation will proceed. 
For details on obtaining the informed consent see Chapter 10.1. 
 Overview of medical care about the study participant 
Patient in both arms will receive the best standard of care. General supportive care guided by 
official recommendations and local protocols will be given, as described in Chapter 5.6.  
The centres are encouraged to follow appropriate antibiotic stewardship practices, e.g. 
guidelines 
for 
hospital-acquired 
and 
ventilator-associated 
pneumonia 
(VAP/HAP) 
management (15). As for ventilation strategies, the centres are encouraged to comply with the 
best evidence of ventilator settings for ARDS patients, i.e. tidal volume approx. 6 mL/kg of 
predicted body weight, driving pressure (∆P) < 15 cm of water, plateau pressure (Ppl) < 30 cm 
of water, setting inspiratory fraction of oxygen (FiO2) and positive end-expiratory pressure 
(PEEP) to keep SaO2 ≥ 90% or PaO2 ≥ 8 kPa and set respiratory rate (RR) to maintain pH ≥ 
7.20. Beside ventilator settings, other measures are left to the local protocols and at the 
discretion of each centre, e.g. prone positioning, neuromuscular blocking agents, lung 
recruitment manoeuvres, and extracorporeal membrane oxygenation (ECMO).  

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Weaning from mechanical ventilation is performed by the daily screening of readiness through 
using the spontaneous breathing trial (SBT) described in APPENDIX B Assessment 
tools, 
scores, and scales, Chapter 14.2. If SBT is successful and no other significant reason against 
extubation is present, the patient is extubated. Patients allowed spontaneous ventilation while 
on ECMO are classified as support dependent until ECMO is weaned off. 
 Clinical examinations and assessments 
During the trial course, subjects will be monitored during hospitalization and after discharge. A 
summary of scheduled procedures is outlined in Chapter 6.4. For a graphic summary see 
Table 1. 

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Table 1: Clinical trial schedule 
 
STUDY PERIOD 
 
Enrolment 
Allocation 
Post-allocation 
Prim. endpoint 
Follow-up 
Premature termination 
TIMEPOINT 
0–24h 
 
D1 
D2 
D3 
D5 
D10 
D14 
D28 
D60 
D90 
D180 
D360# 
Anytime 
ENROLMENT: 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
INTERVENTIONS: 
 
Dexamethasone 20 mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dexamethasone 6 mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ASSESSMENTS: 
 
Demographic data2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs4 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood count and routine biochemistry5 
 
 
X  
  
 
 
 
 
 
 
 
 
 
 
APACHE II6 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Ventilatory status 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
COV-HI7 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inflammatory markers8 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
WHO CPS9 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Hospitalization status 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
Vital status 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Barthel index10 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Reason for premature termination 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1 hCG from peripheral blood sample in women with childbearing potential  
2 Age, sex, race or ethnic group, BMI  
3 Allergies, comorbidities, and Charles comorbidity index (CCI, Chapter 14.2.3), chronic medication  
4 Temperature, blood pressure, heart rate, respiratory rate 
5 Blood count (RBC, WBC, haematocrit, lymphocyte count, platelets), coagulation profile, renal and liver functions (BUN, creatinine, bilirubin, AST, ALT), D-dimer, LDH, troponin, pH, blood 
gases, sodium, potassium, chloride, glycaemia (other laboratory tests and imaging methods are left at the discretion of each centre) 
6 Counted using the worst values in the first 24 h of ICU stay – for details See APPENDIX B, Chapter 14.2.1 
7 D1 – CRP, ferritin, D2 – CRP; COV-HI is defined as CRP ≥ 150 mg/L or doubling within 24 h from greater than 50 mg/L, or ferritin ≥ 1500 μg/L (12,16,17) 
8 CRP (other markers e.g. procalcitonine, presepsin, interleukin-6 at the discretion of each centre) 
9,10 See APPENDIX B, Chapter 14.2  
 
 
 
 
 
 
 
 
 
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 Study procedures 
At enrolment 
• 
Eligibility screen – inclusion and exclusion criteria 
• 
Informed consent procedure (Chapter 10.1) 
• 
Pregnancy testing from blood sample (hCG) in women with childbearing potential 
• 
Demographic data (age, sex, race or ethnic group, BMI) 
• 
Medical history (allergies, comorbidities and CCI, chronic medication) 
• 
Vital signs (temperature, blood pressure, heart rate, respiratory rate) 
Day 1 
• 
Vital signs (temperature, blood pressure, heart rate, respiratory rate) 
• 
Administration of dexamethasone according to the allocation to treatment arms 
• 
Blood count and routine biochemistry [RBC, WBC, haematocrit, lymphocyte count, 
platelets, coagulation profile, renal and liver functions (BUN, creatinine, AST, ALT, 
bilirubin), D-dimer, LDH, troponin, pH, blood gases, sodium, potassium, chloride, 
glycaemia]  
• 
Inflammatory markers (CRP; other markers e.g., procalcitonine, presepsin, interleukin-
6 at the discretion of each centre) 
• 
COV-HI assessment (APPENDIX B, Chapter 14.2.4) – based on Day 1 CRP or ferritin 
level; 
• 
APACHE II score counted using the worst values in the first 24 h of ICU stay (the score 
is determined based on specific parameters from medical history, vital signs, blood 
count and biochemistry, and other examinations; APPENDIX B, Chapter 14.2.1) 
Day 2 
• 
Administration of dexamethasone according to the allocation to treatment arms 
• 
Inflammatory markers (CRP; other markers e.g., procalcitonine, presepsin, interleukin-
6 at the discretion of each centre) 
• 
COV-HI assessment (APPENDIX B, Chapter 14.2.4) – based on Day 2 CRP level. 
Day 3 to Day 10 
• 
Administration of dexamethasone according to the allocation to treatment arms 
• 
Inflammatory markers (CRP; other markers e.g., procalcitonine, presepsin, interleukin-
6 at the discretion of each centre) 
Day 14 
• 
World Health Organization Clinical Progression Scale (APPENDIX B, Chapter 14.2.7) 
• 
Inflammatory markers (CRP; other markers e.g., procalcitonine, presepsin, interleukin-
6 at the discretion of each centre) 
Day 1 to Day 28 / ICU discharge (whichever comes first) 
• 
Checking adverse events and adverse reactions (with special interest in newly 
emerged infections and new thrombotic complications) 
• 
Ventilatory status, i.e. use of a mechanical ventilator or other ventilation/oxygen support 
• 
Vital status 
• 
Discharge from ICU and hospital 

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Days 60, 90, 180, 360 
• 
Out-patient visits (if possible) OR structured phone call interviews lead by study nurse 
with the patient or his/her family member or caregiver 
• 
Vital status 
• 
Quality of life by the assessment of daily life activities and functional independence 
(Barthel Index; APPENDIX B, Chapter 14.2.2) 
• 
Checking adverse events and reactions 
 Biological samples 
Blood samples will be taken following local practice and analysed in the respective clinical 
laboratory facility of the trial centre. No other biological specimens will be obtained or stored in 
this trial. 
 Assessment tools, scores, and scales 
The following tools will be used during the trial and are described in APPENDIX B
 
Assessment tools, scores, and scales, Chapter 14.2): 
• 
APACHE II 
• 
Barthel index 
• 
Charlson comorbidity index 
• 
COV-HI 
• 
Glasgow coma scale 
• 
Spontaneous breathing trial 
• 
WHO CPS 
7. SAFETY ASSESSMENTS 
Before the start of the clinical trial, all Investigators will undergo training in pharmacovigilance 
requirements and obtain detailed written instructions for recording and reporting of AEs. These 
instructions for pharmacovigilance will be part of the Investigator's Site File. 
 Definitions (according to the Directive 2001/20/EG) 
For clinical trials, effective legislation has introduced the following definitions. 
 
 
 
 
 
 

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Table 2: Definitions of safety signals in clinical trials 
Adverse event 
AE 
Any untoward medical occurrence in a patient or clinical 
trial subject administered a medicinal product and which 
does not necessarily have a causal relationship with this 
treatment. 
Adverse drug reaction 
ADR 
All untoward and unintended responses to an 
investigational medicinal product related to any dose 
administered 
Serious adverse event 
SAE 
A serious adverse event/reaction is any untoward medical 
occurrence or effect that at any dose: 
• 
Results in death; 
• 
Is life-threatening; 
• 
Requires hospitalization or extension of existing 
hospitalization; 
• 
Results in persistent or significant disability or 
incapacity; 
• 
Is a congenital anomaly or birth defect. 
Serious adverse 
reaction 
SADR 
Unexpected adverse 
reaction 
UADR 
Adverse reaction, the nature, severity, or outcome of which 
is not consistent with the product information (SmPC) 
Suspected unexpected 
serious adverse 
reaction 
SUSAR 
Any suspected adverse reaction related to the study 
treatment that is both serious and unexpected. 
 AE surveillance, recording and documentation 
AE could be diseases or symptoms which occur or worsen after the enrolment of a patient in 
the clinical trial. All AEs need to be documented, no matter if the investigator suspects a causal 
connection to the study medication. AE will be monitored and documented from the day of 
giving informed consent until the end of participation in the study (i.e., Day 360).  
Subjects will be instructed to report any AEs that they experience to the investigator. 
The investigator should actively ask about AEs. 
Each AE should be described, documented in the eCRF, and evaluated to determine: 
• 
Seriousness (see Chapter 7.4); 
• 
Severity (see Chapter 7.5); 
• 
Causality, i.e. relation to the study medication (see Chapter 7.6.); 
• 
Duration (start and end dates or whether it continues). 
• 
Action taken (no action taken; study medication discontinued; prolongation of the 
ongoing hospitalization; administration of a drug etc.) 
AE needs to be followed until its resolution, i.e. until it subsides, stabilizes, becomes chronic, 
or the subject dies. 
If AE fulfils the criteria of SAE, a separate form must be completed besides the standard eCRF 
record (see Chapter 7.7).  
AEs will be recorded according to the Medical Dictionary for Regulatory Activities (MedDRA). 
The most recent MedDRA version at the start of the study will be used. 
 

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 Treatment of AE 
A patient with an AE must receive appropriate therapy. The investigator may decide to 
discontinue the study medication. The patient will remain under medical supervision until the 
investigator believes that the AE has been resolved. 
 Assessment of seriousness 
AE is considered serious if it fulfils the definition in Chapter 7.1. 
Some situations can be considered as SAE even if they do not fulfil the criteria of the 
definition. These are important medical events that may not be immediately life-threatening, or 
result in death, or hospitalization but may jeopardize the subject, or may require intervention 
to prevent one of the other outcomes listed in the definition above. These should also be 
considered SAE – e.g., allergic bronchospasm, convulsions, or other states requiring 
treatment. 
If AE fulfils the criteria of SAE, a separate Serious Adverse Event Form must be completed 
and sent to the sponsor. For the procedure see Chapter 7.7. 
In this clinical trial, the following SAE are excluded from the notification requirement: 
• 
SAE which occurs after enrolment (i.e., after giving informed consent), but before the 
study medication was initiated; 
• 
Hospitalization(s) planned before the enrolment; 
• 
Death not related to the dexamethasone use. 
 Assessment of intensity (severity) 
The intensity (severity) of an AE should be evaluated according to these 5 categories: 
Grade 1 
AE is asymptomatic or mildly symptomatic, requires only observation, no medical 
intervention 
Grade 2 
AE with medium intensity, requires local, non-invasive, or small-scale treatment 
Grade 3 
AE is medically significant, requires hospitalization or extension of ongoing 
hospitalization, but it is not directly life-threatening 
Grade 4 
AE is life-threatening and requires urgent significant medical intervention 
Grade 5 
AE leads to death 
 Assessments of causality 
To assess the relation between administration of the study medication and the AE, the 
following definitions apply: 
• 
Related – The event is known to occur with the study medication, there is a reasonable 
possibility that the study medication caused the AE, or there is a temporal relationship 
between the study medication and AE. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study medication and the AE.  

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• 
Not related – There is not a reasonable possibility that the administration of the study 
medication caused the AE, there is no temporal relationship between the study 
medication and AE onset, or an alternate aetiology has been established. 
 Reporting of SAE and SUSAR 
If at that point all required information is not available, succeeding records will be sent by the 
investigator. Sponsor will check the notification completeness and formal plausibility. If 
required, queries will be made and followed up. 
In the case of death, a copy of the autopsy record should be added. If the death of the subject 
complies with the definition of SUSAR (see Chapter 7.1), it will be reported as SUSAR (see 
below). 
Sponsor has full responsibility for the safety of the clinical trial. Further reporting of AEs to the 
competent authorities according to the legal requirements is the responsibility of the sponsor. 
Follow-up 
All SAEs should be followed until their resolution, i.e., they subside, stabilize, become chronic, 
or the subject dies followed. In case of early termination because of SAE occurrence, the 
subject should be followed until SAE resolution. All necessary extra visits will be recorded in 
the eCRF as "Unscheduled visits". 
Follow-up information is sent using a new SAE Form stating that this is a follow-up to the 
previously reported SAE and giving the date of the original report. Within 24 hours of receipt 
of follow-up information, the investigator must update the SAE form and submit any supporting 
documentation (e.g., laboratory test reports, subject discharge summary, autopsy report etc.) 
The follow-up information should describe whether the event has resolved or continues, if and 
how it was treated and whether the patient continued or withdrew from trial participation.  
Reporting of SUSAR 
SAE related to the study medication fulfilling the criterion of unexpectedness (i.e., SUSAR) 
must be reported by the sponsor to the Ethics Committee and the EudraVigilance database 
(module EVCTM), at the latest 15 days after it becomes known. Sponsor will also inform all 
Investigators involved in the trial. Reporting to the EudraVigilance database will be performed 
via regulatory authority according to the agreement between the sponsor and the regulatory 
authority. In case of a fatal or life-threatening SUSAR, the sponsor will report all relevant 
The Investigator is obliged to report any SAE within 24 hours after he/she learns 
about it to the Sponsor using Serious Adverse Event Form (SAE Form). The blank 
forms are stored in the Investigator’s Site File. The announcement will be done by 
e-mail: farmakovigilance@med.muni.cz AND nerusilova@med.muni.cz. 
Person responsible for pharmacovigilance 
MUDr. Kateřina Nerušilová 
Tel: +420 737 657 454 
E-mail: farmakovigilance@med.muni.cz  
E-mail: nerusilova@med.muni.cz  
Deputy to the responsible person 
MUDr. Jana Vinklerová, Ph.D. 
Tel: +420 602 650 094 
E-mail: farmakovigilance@med.muni.cz  
E-mail: jvinkler@med.muni.cz  

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information immediately, at the latest 7 days after the event becomes known. Any subsequent 
additional information is forwarded within the next 8 days if necessary.  
 Pregnancy 
Pregnant or breastfeeding women cannot be included in the study. Pregnancy testing (hCG, 
blood sample) is obligatory at enrolment in women of childbearing potential (i.e. from menarche 
to the onset of postmenopausal state). In case the information regarding menstrual cycle 
cannot be obtained from the patient due to her health or consciousness status, pregnancy 
testing is also necessary.  
Participants, men and women, must comply with the required 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 for this clinical trial. Newly-emerged 
pregnancy in the hospitalization phase of the trial is highly unlikely. However, if it is diagnosed, 
dexamethasone treatment must be stopped. If a participant becomes pregnant during the 
follow-up phase, she must inform the investigator. 
Pregnancy should be followed by the investigator until completion. If it ends for any reason 
before the anticipated date, the investigator should notify the sponsor. At the completion of the 
pregnancy, the investigator will document the outcome of the pregnancy. If the outcome of the 
pregnancy meets the criteria for classification as SAE (e.g., spontaneous abortion, stillbirth, 
neonatal death, postpartum complication, or congenital anomaly), the investigator should 
follow the procedures for reporting an SAE (see Chapter 7.7). 
8. STATISTICS 
A separate Statistical Analysis Plan (SAP) and Statistical Interim Analysis Plan (SIAP) will be 
prepared to provide details on the approach to analyses. The SAP will be finalized before the 
interim database lock. All eventual deviations from the SAP will be described and justified in 
the relevant part of The Clinical Trial Report. 
 Sample size determination 
The sample size was calculated to detect the difference of 3 VFDs at 28 days (primary efficacy 
endpoint) between the two treatment arms at two-sided type I error of 0.05 and power of 80%. 
Based on data from a multi-centre randomized controlled trial in COVID-19 ARDS patients in 
Brazil (7) and the multi-centre observational study from French and Belgian ICUs regarding 
moderate to severe ARDS related to COVID-19 (18), investigators assumed standard 
deviation of VFD at 28 days as SD=9. Using these assumptions, a total of 142 patients per 
treatment arm would be needed, after adjustment for drop-out rate, 150 per treatment arm (300 
patients per study) will be enrolled. 
 
The Investigator should report the pregnancy to the Sponsor within 24 hours of 
learning of its occurrence using Pregnancy Form. This announcement will be done 
by e-mail: farmakovigilance@med.muni.cz AND nerusilova@med.muni.cz. 

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 Analysis of efficacy 
Primary efficacy endpoint (number of VFDs at day 28) will be calculated for both treatment 
arms separately with corresponding 95% confidence intervals. Comparison between arms will 
be based on parametric or non-parametric test (following the type of data distribution) and will 
be adjusted for relevant baseline covariates (stratification parameters)  
Secondary and exploratory efficacy endpoints will be analysed following the type of data (Chi-
square test or Fisher's exact test for binary data and ANOVA or a non-parametric alternative 
tests for continuous and ordinal data, if appropriate).  
The primary population for analysis of efficacy will be Intention-To-Treat population (ITT), and 
results will be confirmed on the Per-Protocol Population (PP). 
8.2.1. Subgroup analysis 
Pre-planned subgroup analysis will be performed regarding the primary outcome variable in 
the subgroups defined by the following criteria: 
• 
Age  
• 
Sex 
• 
BMI 
• 
Comorbidities  
• 
P/F ratio  
• 
Length of dexamethasone treatment before enrolment 
• 
ECMO procedure 
No adjustments of p-values due to multiplicity are planned.  
 Analysis of safety 
The safety will be analysed in all patients who received any dose of study treatment and 
provided at least one post-dose safety assessment (Safety Population). All adverse events will 
be coded and tabulated by system organ class and preferred term for individual events within 
each system organ class and will be presented in descending frequency. Adverse events will 
also be tabulated by severity and relationship to the study medication. Serious adverse events 
will be summarized separately. 
 Planned interim analysis 
One interim analysis is planned for safety and efficacy evaluation after the primary outcome is 
known for the 150th subject (50% of planned sample size). To control the overall level of type 
I error, the P value of 0.01 for interim analysis and 0.04 for the final analysis will be applied. All 
the details on stopping rules for interim analysis will be described in SIAP.  
The interim analysis will be evaluated and decision about continuation of the study will be done 
by DMC. 
 Missing data 
No imputation techniques for missing data will be applied. 
 

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9. DATA MANAGEMENT AND QUALITY ASSURANCE 
 eCRF database  
All participants will be assigned an identification code to ensure the pseudonymization of their 
data. The investigator will maintain a subject identification list for the trial centre (subject 
identification codes with the corresponding subject names) to enable records to be identified. 
Trial data will be collected in eCRFs managed in electronic data capture system REDCap. 
Access to the database (username, password) will be granted by the study data manager, and 
the respective study staff will be trained for using it right and safely. The investigator is 
responsible for the data correctness, completeness, and filling in time. eCRF will be designed 
to generate queries on missing data or unusual data entries, which will be fed back to the study 
site investigators in regular intervals.  
 Trial documents, medical records 
The sponsor, the trial site and study staff will handle the subject's personal and trial data 
according to the effective legislation regarding data protection. Any paper or electronic trial 
documents or data are confidential and must not be disclosed to the third persons. In the 
informed consent form, the participants are informed that their medical records can be provided 
only to the authorized monitors, auditors, or inspectors.  
Medical records of the subjects will be retained in the trial site for 15 years (from the end of the 
clinical trial), so will be the relevant trial administrative documents at the sponsor's side.  
 Monitoring and auditing 
The trial centre will be monitored according to the Monitoring plan. The objectives of the 
monitoring are to ensure that the trial participant's safety and rights are respected, that 
accurate, valid and complete data are collected, and that the trial is conducted in accordance 
with the trial protocol, the principles of GCP and national legislation. The investigator agrees 
that the monitor will regularly visit the trial centre and will be given appropriate support (e.g., 
the access to all necessary documents incl. patient's medical records). A report on the 
progress, findings and resolution of any discrepancies will be prepared from each monitoring 
visit. The investigator undertakes to read the monitoring report and to ensure that any possible 
discrepancies are corrected. Sponsor, Regulatory authority and Ethics committees have the 
right to inspect/audit the trial site. The investigator undertakes to co-operate will the 
inspectors/auditors. 
 Steering committee 
The Steering Committee is constituted by all study investigators of the REMED trial. It is 
responsible for the development of the study protocol, continuous and final results 
interpretations and manuscripts preparation. The Steering Committee closely collaborates with 
independent Data monitoring committee and the sponsor. 
 Data monitoring committee 
Members of data monitoring committee (DMC) are experts in intensive care medicine which 
are not involved in the REMED trial and an independent statistician. DMC is responsible for 
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the sponsor regarding the safety and continuation of the trial based on evidence of possible 
significant differences between intervention and control group. Members of DMC are listed in 
a separate document. 
10. 
ETHICAL ASPECTS 
This trial will be conducted following the applicable legislation and requirements for good 
clinical practice according to the ICH E6(R2). Compliance with this standard provides public 
assurance that the rights, safety and well-being of trial participants are protected and that the 
clinical trial data are credible. All essential trial documents and their potential amendments will 
be submitted to the relevant Ethics committee and Regulatory authority for approval. 
 
Informed consent procedure 
The investigator assesses patient’s ability to decide and extent of potential consciousness 
impairment based on GCS and other appropriate clinical measures (at discretion of the trial 
centre). 
10.1.1. Fully conscious and oriented patients (GCS 15) 
Patient with decision-making capacity will go through the standard procedure (informative 
interview with the investigator, written information for the patients, the possibility to ask 
questions, and adequate time to discuss with family and decide). If the patient wishes to 
participate, he/she will provide written prospective informed consent. 
10.1.2. Patients with limited ability to decide (GCS 14 or 13) 
Some patients may be limited in their decisional capacity due to their acute health status, or 
medication. Generally, if a patient understands simplified information and can communicate 
verbally, the simplified procedure of obtaining informed consent will be applied. The shortened 
(one-page) information sheet and consent form for signature will be used.  
As soon as the patient regains full decisional capacity, he/she will be approached to provide 
consent with the continuation of his/her participation in the trial. Patients will be informed about 
the option to withdraw from the trial. Patients who decide to terminate their involvement can 
permit the sponsor to use the data collected, or they can ask for deleting all data collected. 
Both options will be presented to them. 
If the patient does not regain a decisional capacity, the initial consent will remain valid. 
10.1.3. Patients lacking the capacity to decide (GCS 12 or less) 
It is expected that a significant proportion of screened patients will lack the capacity to provide 
informed consent due to severely altered consciousness, severe respiratory distress, or 
sedation necessary to facilitate mechanical ventilation. In this situation, the deferred consent 
policy will be applied. Such a patient will be enrolled after independent physician witnesses (in 
writing) that the patient cannot give his/her consent and fulfils eligibility criteria.  
Patient's close person (spouse/partner, close relative, caregiver) will be informed about the 
patient's enrolment and the nature of the study. If possible and compliant with the 
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for an informative interview, to obtain the information leaflet, and to sign a confirmation that 
he/she was informed about the patient's participation in the trial. 
As soon as the patient regains decisional capacity, he/she will be approached to provide 
consent with the continuation of his/her participation in the trial. Patients will be informed about 
the option to withdraw from the trial. Patients who decide to terminate their involvement can 
permit the sponsor to use the data collected, or they can ask for deleting all data collected. 
Both options will be presented to them. 
If the patient does not regain a decisional capacity, the initial consent by an independent 
physician will remain valid. 
 
Supervision of the informed consent procedure 
The process of obtaining informed consent from a patient or an independent physician must 
always be appropriately documented by the investigator through valid forms and the patient's 
medical records, as well. The clinical trial monitor will check the process during the monitoring 
visits. Important deviations in the process will lead to the termination of the patient’s 
participation in the trial. 
 
Vulnerable population 
Beside patients with diminished decision capacity, other specifically vulnerable participants 
(children, pregnant women, prisoners, refugees, institutionalized patients, patients with severe 
mental illnesses, etc.) will not be enrolled in this clinical trial. 
11. 
PUBLICATION POLICY 
Results of this clinical trial are planned to be published in the medical literature. Any 
publications must be approved by the sponsor and meet the quality requirements for current 
clinical research publications (e.g., CONSORT statement). 
12. 
FINANCING AND INSURANCE 
REMED is an investigator-initiated clinical trial. Funding will be granted from the project 
research infrastructure Czech Clinical Research Infrastructure Network CZECRIN (LM 
2018128) and University Hospital Brno. Trial funders have no role in the study design, 
collection, analysis and interpretation of data. Investigators declare no financial or non-financial 
competing interest regarding the focus of this trial. 
Mandatory insurance of the participants is arranged. The coverage for damages emerging from 
the participation in the clinical trial will be provided according to the applicable legal 
requirements. 
 
 

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13. 
REFERENCES 
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minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis. 
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12.  Barda N, Riesel D, Akriv A, Levy J, Finkel U, Yona G, et al. Developing a COVID-19 mortality risk 
prediction model when individual-level data are not available. Nat Commun. 2020 07;11(1):4439.  
13.  Harhay MO, Casey JD, Clement M, Collins SP, Gayat É, Gong MN, et al. Contemporary strategies 
to improve clinical trial design for critical care research: insights from the First Critical Care Clinical 
Trialists Workshop. Intensive Care Med. 2020;46(5):930–42.  
14.  Therapeutic Management [Internet]. COVID-19 Treatment Guidelines. [cited 2020 Dec 14]. 
Available from: https://www.covid19treatmentguidelines.nih.gov/therapeutic-management/ 

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15.  Torres A, Niederman MS, Chastre J, Ewig S, Fernandez-Vandellos P, Hanberger H, et al. 
International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired 
pneumonia and ventilator-associated pneumonia: Guidelines for the management of hospital-
acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory 
Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of 
Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del 
Tórax (ALAT). Eur Respir J. 2017;50(3).  
16.  Keddie S, Ziff O, Chou MKL, Taylor RL, Heslegrave A, Garr E, et al. Laboratory biomarkers 
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severity 
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17.  Manson JJ, Crooks C, Naja M, Ledlie A, Goulden B, Liddle T, et al. COVID-19-associated 
hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study. Lancet 
Rheumatol. 2020 Oct;2(10):e594–602.  
18.  Grimaldi D, Aissaoui N, Blonz G, Carbutti G, Courcelle R, Gaudry S, et al. Characteristics and 
outcomes of acute respiratory distress syndrome related to COVID-19 in Belgian and French 
intensive care units according to antiviral strategies: the COVADIS multi-centre observational 
study. Ann Intensive Care. 2020 Oct 6;10(1):131.  
 
 

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14. 
SUPPLEMENTS/APPENDICES 
 
APPENDIX A 
Specimen of labelling 
 
 
APPENDIX B 
Assessment tools, scores, and scales 
14.2.1. APACHE II 
The APACHE-II score provides an estimate of ICU mortality based on several laboratory 
values and patient signs taking both acute and chronic disease into account. The score 
consists of the following parameters: age, severe organ insufficiency/immunodeficiency, body 
temperature, mean arterial pressure, heart rate, RR, oxygenation, arterial pH, serum Na, K, 
creatinine, haematocrit, WBC, Glasgow coma scale. More information could be found here: 
https://www.mdcalc.com/apache-ii-score  
Reference: Knaus W. A., Draper E. A., Wagner D. P., Zimmerman J. E. APACHE II: a severity 
of disease classification system. Crit Care Med 1985; 13 (10): 818–829. 
14.2.2. Barthel index 
The Barthel Index evaluates functional limitations in 10 activities of daily living: food intake, 
dressing, locomotion, stair walk, moving from bed to chair, personal hygiene, bathing, toilet 
use, and urine and stool continence. The assessment is performed by a healthcare 
professional. For details please see: https://www.uzis.cz/index.php?pg=registry-sber-dat--
klasifikace--barthelove-test 
Reference: Mahoney F. I., Barthel D. Functional evaluation: the Barthel Index. Maryland State 
Med Journal 1965; 14: 56–61. 
14.2.3. Charlson comorbidity index 
The index quantifies an individual's burden of disease and corresponding mortality risk. It is 
counted from information on age, cardiovascular, neurological, respiratory, gastrointestinal, 
metabolic, kidney and oncological diseases, or AIDS. More information could be found here: 
https://www.mdcalc.com/charlson-comorbidity-index-cci  
EudraCT No. 2020-005887-70 
Klinické hodnocení REMED  
Zadavatel: Fakultní nemocnice Brno, Jihlavská 20, 625 00 Brno 
DEXAMETHASON (ATC KÓD: H02AB02) 
Koncentrace: 4 mg/ml | Léková forma: inj/inf sol 
Pouze pro účely klinického hodnocení. 
Pokyny pro užívání a uchování přípravku – viz SPC a Protokol  
Kód pacienta: 
 
 
Léčebné rameno: 20 | 06 
Centrum KH: název, adresa 
Zkoušející: jméno | e-mail | telefon 

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Reference: Charlson M. E., Pompei P., Ales K. L., MacKenzie C.R. A new method of classifying 
prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 
40: 373–383. 
14.2.4. COV-HI 
A part of COVID-19 patients have a high-risk hyperinflammatory phenotype. The diagnostic 
criteria for COVID-19-associated hyperinflammation are CRP ≥ 150 mg/L or doubling within 
24 h from greater than 50 mg/L or a ferritin ≥ 1500 μg/L. COV-HI is associated with adverse 
outcomes, e.g. mortality and need for escalation of respiratory support. 
Reference: Manson J. J., Crooks C., Naja M., Ledlie A., Goulden B., Liddle T., et al. COVID-
19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal 
cohort study. Lancet Rheumatol 2020;2 (10): e594–602. 
14.2.5. Glasgow coma scale 
The Glasgow coma scale describes the level of consciousness of patients. It consists of the 
assessment of eye opening, verbal manifestation and motor activity of the patient. For details 
please see: https://www.glasgowcomascale.org/  
Reference: Teasdale G., Jennett B. Assessment of coma and impaired consciousness. A 
practical scale. Lancet 1974; 2: 81–84. 
14.2.6. Spontaneous breathing trial 
Spontaneous breathing trial tests the ability of a patient to breathe while recieving minimal or 
no ventilatory support. The accepted modes are disconnection of patient’s artificial airway from 
the ventilator while providing adequate humidity and temperature of inhaled air or keeping the 
patient on ventilator with minimal level of Positive End-Expiratory Pressure (PEEP of 5 cm 
H2O) and Pressure Support (PS of 5 cm H2O) 
Reference:  Yang K, Tobin MJ, A prospective study of indexes predicting the outcome of 
weaning from mechanical ventilation. N Engl J Med 1991; 324: 1445–1450 
14.2.7. WHO Clinical Progression Scale 
The scale provides a measure of illness severity across a range from 0 (not infected) to 10 
(dead). It assesses the clinical state of a patient regarding vital status, confirmation of virus 
RNA, symptoms of infection, hospitalization and the way of breathing support. 
Reference: WHO Working Group on the Clinical Characterisation and Management of COVID-
19 infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet 
Infect Dis 2020; 20 (8): e192–7.