COVID-19-associated ARDS Treated With DEXamethasone: an Open-label, Randomized, Controlled Trial: CoDEX (Alliance Covid-19 Brasil III)
Phase: PHASE3
Conditions: Coronavirus Infection, Pneumonia, Viral, Acute Respiratory Distress Syndrome
Sponsor: Hospital Sirio-Libanes

                      
 
ORIGINAL ARTICLE 
 
COVID-19-associated ARDS treated with DEXamethasone (CoDEX): study 
design and rationale for a randomized trial 
 
Bruno Martins Tomazini1,2, Israel Silva Maia3,4, Flavia Regina Bueno1, Maria Vitoria Aparecida 
Oliveira Silva1, Franca Pellison Baldassare1, Eduardo Leite Vieira Costa1, Ricardo Antonio Bonifácio 
Moura1, Michele Ouriques Honorato1, André Nathan Costa1, Alexandre Biasi Cavalcanti3,4, Regis 
Goulart Rosa4,5, Álvaro Avezum6, Viviane Cordeiro Veiga7, Renato Delascio Lopes8,9, Lucas Petri 
Damiani3, Flávia Ribeiro Machado4,10, Otavio Berwanger11, Luciano César Pontes de Azevedo1,2,4 for the 
COALITION COVID-19 Brazil III Investigators 
 
1. Hospital Sírio-Libanês - São Paulo (SP), Brazil. 
2. Universidade de São Paulo - São Paulo (SP), Brazil. 
3. Research Institute, HCor-Hospital do Coração - São Paulo (SP), Brazil. 
4. Brazilian Research in Intensive Care Network (BRICNet) - São Paulo (SP), Brazil. 
5. Hospital Moinhos de Vento - Porto Alegre (RS), Brazil. 
6. Hospital Alemão Oswaldo Cruz - São Paulo (SP), Brazil. 
7. Hospital Beneficência Portuguesa - São Paulo (SP), Brazil. 
8. Brazilian Clinical Research Institute (BCRI) - São Paulo (SP), Brazil. 
9. Duke Clinical Research Institute, Duke University Medical Center - Durham, United States. 
10. Universidade Federal de São Paulo - São Paulo (SP), Brazil. 
11. Hospital Israelita Albert Einstein - São Paulo (SP), Brazil. 
 
Ethics and dissemination: This trial was approved by the Brazilian National Committee of Ethics in Research 
(Comissão Nacional de Ética em Pesquisa - CONEP) and National Health Surveillance Agency (Agência Nacional 
de Vigilância Sanitária - ANVISA). An independent data monitoring committee will perform interim analyses and 
evaluate adverse events throughout the trial. Results will be submitted for publication after enrolment and follow-
up are complete. 
 
Conflicts of interest: None. 
 
Founding source: This research is funded by Hospital Sírio-Libanês. The Aché Pharmaceutical provided the study 
drug, the drug logistics distribution to the study centers and insurance for the study patients’ but will have no 
participation or interfere with the trial design, enrolment, analysis, manuscript writing, or publication. 
 
Submitted on June 10, 2020 
Accepted on June 18, 2020 
 
Corresponding author:   
Luciano Cesar Pontes de Azevedo  
Hospital Sírio-Libanês  
Rua Daher Cutait, 69  
Zip code: 01308-060 - São Paulo (SP), Brazil  
E-mail: luciano.azevedo@hsl.org.br 
 

                      
 
ABSTRACT 
 
Objective: The infection caused by the severe 
acute respiratory syndrome coronavirus 2 (SARS-
CoV2) spreads worldwide and is considered a 
pandemic. The most common manifestation of 
SARS-CoV2 infection (Coronavirus disease 2019 
- COVID-19) is viral pneumonia with varying 
degrees of respiratory compromise and up to 40% 
of hospitalized patients might develop acute 
respiratory distress syndrome. Several clinical 
trials evaluated the role of corticosteroids in non-
COVID-19 acute respiratory distress syndrome 
with conflicting results. We designed a trial to 
evaluate the effectiveness of early intravenous 
dexamethasone administration on the number of 
days alive and free of mechanical ventilation 
within 28 days after randomization in adult 
patients with moderate or severe acute respiratory 
distress syndrome due to confirmed or probable 
COVID-19. 
Methods: This is a pragmatic, prospective, 
randomized, stratified, multicenter, open-label, 
controlled trial including 350 patients with early-
onset (less than 48 hours before randomization) 
moderate or severe acute respiratory distress 
syndrome, defined by the Berlin criteria, due to 
COVID-19. Eligible patients will be randomly 
allocated to either standard treatment plus 
dexamethasone (intervention group) or standard 
treatment without dexamethasone (control group). 
Patients in the intervention group will receive 
dexamethasone 20mg IV once daily for 5 days, 
followed by dexamethasone 10mg IV once daily 
for additional 5 days or until intensive care unit 
discharge, whichever occurs first. The primary 
outcome is ventilator-free days within 28 days 
after randomization, defined as days alive and free 
from invasive mechanical ventilation. Secondary 
outcomes are all-cause mortality rates at day 28, 
evaluation of the clinical status at day 15 assessed 
with 
a 
6-level 
ordinal 
scale, 
mechanical 
ventilation duration from randomization to day 28, 
Sequential Organ Failure Assessment Score 
evaluation at 48 hours, 72 hours and 7 days and 
intensive care unit -free days within 28. 
 
Keywords: Coronavirus; Respiratory distress 
syndrome, adult; Adrenal cortex hormones; 
COVID-19; Critical care; Dexamethasone 
 
ClinicalTrials.gov identifier: NCT04327401. 
 
INTRODUCTION 
 
In early March 2020, the World Health Organization (WHO) declared the outbreak of a new 
coronavirus a pandemic.(1) This coronavirus, later named severe acute respiratory syndrome coronavirus 
2 (SARS-CoV2), elicited an outburst of severe viral pneumonia (Coronavirus disease 2019 - COVID-
19) in mid-December in the Wuhan province, China.(2) The disease spread worldwide, and after three 
months, countries in all continents, except Antarctica, had registered cases.(3) Considering all cases of 
COVID-19, estimates suggest that 5% will develop respiratory failure,(4) while in hospitalized patients, 
up to 40% might develop acute respiratory distress syndrome (ARDS),(5) which is the leading cause of 
death in this population.(4) 

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Corticosteroids, due to its anti-inflammatory effects,(6) may be a suitable therapy for these patients 
and have been tested in different scenarios of ARDS.(7,8) A recent trial showed that early use of 
dexamethasone is safe and reduces the duration of mechanical ventilation in ARDS patients without 
COVID-19.(9) However, data suggest that corticosteroids use might increase viral load in patients with 
SARS-CoV-1 infection(10) and Middle East respiratory syndrome (MERS)  infection,(11) while a meta-
analysis showed that corticosteroids are associated with increased mortality in influenza pneumonia.(12) 
Early use in less severe cases and late use in the course of ARDS might be responsible for the 
detrimental effects in this population. Current guidelines recommend against using corticosteroids in 
patients with COVID-19 outside clinical trials.(13,14) 
Furthermore, evidence suggests that patients with severe COVID-19 might have a 
hyperinflammatory state known as cytokine storm. The cytokine profile in these patients resembles the 
one found in secondary hemophagocytic lymphohistiocytosis (sHLH),(15) with increased levels of 
interleukin (IL)-2, IL-6 and tumor necrosis factor alpha. Corticosteroids are one of the therapeutic 
cornerstones(16) for treating sHLH.  
Therefore, we propose a pragmatic, randomized, open-label, controlled clinical trial, comparing 
standard treatment versus standard treatment added to early administration of dexamethasone for 10 
days in patients with moderate and severe ARDS due to COVID-19. We used the recommendations for 
Interventional Trials (SPIRIT) guideline for this report,(17) which is presented in the appendix 1 of the 
supplementary material. The steering committee members are shown in the appendix 2 of the 
supplementary material. This manuscript refers to the fifth version of the protocol. 
 
METHODS 
 
The COVID-19-associated ARDS treated with DEXamethasone: CoDEX is a pragmatic, prospective, 
randomized, stratified, multicenter, open-label, superiority, controlled trial including 350 patients with 
moderate or severe ARDS due to confirmed or probable COVID-19 in 51 intensive care units (ICU) in 
Brazil. 
We hypothesize that early administration of dexamethasone increases the number of days alive and 
free of mechanical ventilation in adult patients with moderate or severe ARDS due to SARS-CoV2. The 
trial is registered with ClinicalTrials.gov (NCT04327401).  
Our primary objective is to evaluate the effectiveness of early intravenous (IV) dexamethasone 
administration on the number of days alive and free of mechanical ventilation within 28 days after 
randomization in adult patients with moderate or severe ARDS due to confirmed or probable COVID-
19. Ventilator-free days (VFD) is defined as being free from invasive mechanical ventilation for at least 
48h (successful extubation).(18) If the patient is re-intubated within 48 hours of the extubation it will be 
treated as zero VFD; if re-intubated after 48 hours, the 48 hours period will be counted as VFD.  Patients 

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discharged from the hospital alive before 28 days are considered alive and free from mechanical 
ventilation at day 28. Non-survivors at day 28 are considered to have zero VFD. 
Secondary objectives are to evaluate the effect of dexamethasone treatment plus standard treatment 
versus standard treatment alone on the following: 
- All-cause mortality rates at 28 days after randomization 
- Clinical status of patients at 15 days after randomization using the World Health Organization 6-
point Ordinal Scale for clinical improvement (Table 1) 
- Number of days of mechanical ventilation from randomization to day 28 
- ICU free days within 28 days 
- Change in the Sequential Organ Failure Assessment (SOFA) Score 48 hours, 72 hours and 7 days 
after randomization 
 
Time schedule and study duration 
The planned study duration is five months, being three months of recruitment, one month of follow 
up and one month for data analysis and manuscript writing. The first patient was enrolled on April 17th. 
The final report and publication are expected to be available on the second half of 2020. 
 
Eligibility criteria 
We will include critically ill patients with ARDS due to confirmed or probable COVID-19 admitted 
to the ICU. Probable COVID-19 is defined by the presence of symptoms, which are contemplated in the 
inclusion criteria, travel or residence in a city where community transmission is reported or contact with 
a confirmed case in the last 14 days prior symptoms onset(19) and radiological imaging findings 
compatible with COVID-19 at the time of inclusion.  
After 182 patients have been enrolled, the Steering Committee suggested specific changes on both 
inclusion and exclusion criteria. The timing of ARDS diagnosis for inclusion changed from 24 hours to 
48 hours. The rationale for this modification was due to most centers receiving patients intubated in the 
ICU already with ARDS diagnosis and more than 24 hours of mechanical ventilation, which shortened 
the time window for recruitment. Additionally, given the widespread use of corticosteroids before ICU 
admission in Brazil, we allowed inclusion of patients who have previously received one day of 
corticosteroids during hospital stay, which was not allowed at first. The exclusion criteria were refined 
by adding three more criteria: use of immunosuppressive drugs, cytotoxic chemotherapy in the past 21 
days, and neutropenia due to hematological or solid malignancies with bone marrow invasion.  
Each patient must fulfil all the following inclusion criteria to be eligible for enrolment: 
- Age ≥18 years old 
- Probable or confirmed infection by SARS-CoV2 
- Intubated and mechanically ventilated 
- Moderate or severe ARDS according to Berlin criteria(20) (Table 2) 

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- Onset of moderate or severe ARDS in less than 48 hours before randomization 
 
Exclusion criteria are: 
- Pregnancy or active lactation 
- Known history of dexamethasone allergy 
- Daily use of corticosteroids in the past 15 days 
- Indication for corticosteroids use for other clinical conditions (e.g refractory septic shock) 
- Patients who did use corticosteroids during hospital stay for periods equal or greater than two days 
- Use of immunosuppressive drugs 
- Cytotoxic chemotherapy in the past 21 days 
- Neutropenia due to hematological or solid malignancies with bone marrow invasion 
- Patient is expected to die in the next 24 hours 
- Consent refusal for participating in the trial 
 
Study protocol 
Randomization and allocation concealment 
Patients are eligible for enrolment if all the inclusion criteria and none of the exclusion criteria are 
met. Patients are being randomized in a 1:1 ratio to one of the two groups (Figure 1): standard treatment 
plus dexamethasone (intervention group) and standard treatment without dexamethasone (control 
group). The randomization list is generated by an independent statistician in random blocks of 2 and 4 in 
order to preserve the allocation concealment and is stratified by center. Randomization is performed by 
an online web-based central, available 24 hours a day. The group treatment is disclosed to the 
investigator only after all information regarding patient enrolment is recorded in the online system. 
Patients are screened for enrolment by the principal investigator and the research team at each study 
center. 
 
Blinding 
This is an open-label trial where the investigators, caregivers and patients are not blinded regarding 
the intervention. All statistical analyses will be performed in a blinded manner with respect to group 
allocation. 
 
Trial intervention and treatment strategy 
Each ICU enrolling patients in the trial are encouraged to follow the best practice guidelines and their 
institutional protocol for the care of critically ill patients with COVID-19. Laboratory testing, 
hemodynamic management, ventilatory strategy, antibiotics usage, venous thromboembolism and stress 
ulcer prophylaxis, along with all other ICU interventions are left at the discretion of the ICU team for 
both intervention and control group. 

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Patients in the intervention group are receiving after randomization dexamethasone 20mg 
intravenously once daily for 5 days, followed by dexamethasone 10mg intravenously once daily for 
additional 5 days or until ICU discharge, whichever occurs first. Patients in the control group are not 
receiving dexamethasone.  
Although we are not controlling the ventilatory strategy in both groups, physicians are encouraged to 
comply with the following ventilator strategy: tidal volume (Vt) of 4 - 6mL/kg of predicted body weight, 
a plateau pressure < 30cmH20, driving pressure < 15cmH20, respiratory rate to maintain arterial pH > 
7.2 and fraction of inspired oxygen (FiO2) and positive end-expiratory pressure (PEEP) to keep oxygen 
saturation (SpO2) ≥ 88% or partial pressure of oxygen (PaO2) ≥ 55mmHg. Sedation drugs and the use of 
other strategies for ARDS management such as use of neuromuscular blocking agents, prone 
positioning, nitric oxide and extracorporeal membrane oxygenation (ECMO) are left to physicians’ 
discretion and are registered daily on the study’s electronic case report form (eCRF). Each center is 
encouraged to follow institutional guidelines for liberation of mechanical ventilation. The study timeline 
is shown in figure 2. 
 
Procedure to COVID-19 diagnosis 
Due to the possibility of false negative tests, especially on the first days of symptoms,(21) associated 
with different sensitivities depending of the site of collection, patients with negative laboratory tests 
included in the study are evaluated by a blinded committee formed by two critical care physicians of the 
research group with experience treating COVID-19 patients (Adjudication Committee). This committee 
will take into account the timing of testing, clinical symptoms and analysis of chest image (computed 
tomography scan of the lungs, or chest X-ray) to define if the patients has COVID-19 infection with 
negative laboratory tests (probable COVID-19 infection) or if the patient possibly has not COVID-19 
infection. Patients with positive polymerase chain reaction (PCR) tests for SARS-CoV2 are deemed to 
have confirmed COVID-19 infection. 
The main analysis will be based on the intention-to-treat principle, with additional sensitivity 
analysis regarding the COVID-19 infection status (confirmed vs not confirmed).  
 
Adverse events 
The most common adverse effects of corticosteroids use are hyperglycemia and possible increase in 
infections rates. Data on glycemic control is collected daily until day 14 and data on the development of 
new infections is collected daily until day 28. For any other adverse events a specific form is available 
on the eCRF and the data is sent in real time to the coordinating center. 
 
Handling of protocol deviations 
Adherence to protocol and corticosteroids use in both groups is accessed daily. The use of 
corticosteroids in the control group is not forbidden since critically ill patients might have another 

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indication for corticosteroid use during their ICU stay. However, any use of corticosteroids for treating 
ARDS and or refractory hypoxemia in the control group is considered protocol deviation. Changes in 
dosage of dexamethasone or early interruption in the intervention group will also be considered protocol 
deviation. 
If during the trial the patient is deemed to not have COVID-19 infection, which is defined by a 
negative laboratory tests along with negative evaluation by the Adjudication Committee, the study drug 
will be stopped, data on these patients will be collected until day 28 and will be included in the final 
analysis. However, giving the epidemiological context and inclusion criteria, it is expected that only a 
minority of patients will be in this group. 
All centers will receive an initial training session before initiating recruitment to ensure consistency 
of the study procedures and data collection.  
 
Data collection and management 
Unidentified patient data will be collected through an electronic online data capture tool 
(REDCap).(22,23) Demographic and baseline data, height, Simplified Acute Physiology Score (SAPS) 3, 
use of corticosteroids prior the randomization, and the HScore for diagnosis of secondary 
hemophagocytic lymphohistiocytosis (Table 3) are collected for all patients. The SOFA score is 
collected on days 1, 2, 3 and 7. Data from gas exchange, lung mechanics, hemodynamic, laboratory 
data, use of neuromuscular blocking agents, prone positioning and use of ECMO are collected prior 
randomization and until day 14.  
The use of mechanical ventilation or any other ventilation/oxygen support (high flow nasal cannula, 
non-invasive ventilation, use of supplementary oxygen) and data on the 6-point Ordinal Scale (Table 1) 
are collected daily until day 28 or until hospital discharge whichever comes first. Vital status at ICU and 
hospital discharge and any other relevant clinical data such as nosocomial infections, insulin use for 
glycemic control, antibiotic use, and other therapies for COVID-19 (hydroxychloroquine, chloroquine 
and azithromycin) are collected.  
Data on mechanical ventilation are collected in specific forms with data on date and time of initiation 
and discontinuation of therapy. 
All data are collected through the eCRF and periodically data quality checks will be performed by 
the Trial Management Committee. Database lock will be carried out after the 28-day outcome is 
obtained for all patients. Database access will be granted only to steering committee members and 
statisticians before the main results are published. We plan to share data with other ongoing clinical 
trials on the same topic for individual patient´s metanalysis. We plan to upload the study dataset to a 
public database 3 months after database lock. 
 
 
 

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Statistical analysis 
Sample size calculation  
There is a lack of reliable data available in patients with ARDS due to COVID-19 to allow an 
accurate sample size calculation. We therefore used data from a randomized controlled trial in non-
COVID-19 ARDS patients,(24) a well-designed multicenter trial that is representative of ARDS outcomes 
in Brazil, to calculate the sample size. We assumed a mean of VFD at 28 days of 8 days ± 9 days 
(standard deviation) in the control group. With a two-sided type I error of 0.05 and power of 80% to 
identify a difference in three days free of mechanical ventilation between groups, a sample size of 290 
patients would be needed. However, in the end of May 2020, before the first interim analysis, after 
discussing the protocol with the Data Monitoring Committee (DMC), the Steering Committee decided to 
increase the sample size based on the following rational: Given the uncertainty regarding the normality 
of distribution of VFD, based on the Pitman Asymptotic Relative Efficiency,(25) the sample size should 
be increased by 15% to preserve study power coupled with a 4% increase considering possible lost to 
follow-up and withdrawal of consent. Therefore, a final sample size of 350 patients is needed. 
Also, due to the lack of data about ventilator free days in COVID-19 patients, the sample size will be 
updated using the pooled standard deviation of ventilator free days of the first interim analysis, unless by 
the time of the first interim analysis all patients have been recruited.  
The minimal clinically important difference of three days for VFD was chosen based on other 
trials(26,27) along with what is perceived as a significant improvement to the in-hospital complications, 
costs, and intensive care unit availability, especially in countries with limited resources. 
 
Interim analysis and safety 
Two interim analyses are planned for safety and efficacy evaluation, after 96 patients and 234 
patients with the complete follow up to the primary outcome. Based on the results of these interim 
analyses, the DMC will decide if there is proof beyond a reasonable doubt that the intervention is 
effective or not safe in this population. The stopping rule for safety will be a p-value < 0.01 and for 
efficacy p-value < 0.001 (Haybittle–Peto boundary). The Haybittle–Peto boundary is a conservative 
stopping rule at interim analysis that has minimal impact in increasing type I error in two-arm trials.(28) 
The interim analyses will be performed by an external and independent DMC. 
 
Statistical methods 
Main analyses will follow the intention-to-treat principle. For the primary outcome, a generalized 
linear model will be built with beta-binomial distribution or zero/one inflated beta distribution, with 
center as random effect and adjusted for age, corticosteroid use before randomization and PaO2/FiO2 
ratio. The effect size will be estimated as mean difference, the respective 95% confidence interval, and 
hypothesis testing. Missing data on the primary outcome will be dealt with using multiple imputation 
techniques. 

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For details regarding the analysis of the secondary outcomes and other analysis, please refer to the 
Statistical Analysis Plan (SAP) on the appendix 3 of the supplementary material. 
The significance level for all analyses will be 0.05. There will be no adjustment for multiple testing. 
All analyses will be performed using the R software(29) (R Core Team, Vienna, Austria, 2020).  
 
Subgroup and sensitivity analyses 
We plan to perform subgroup analysis for the primary endpoint, including interaction parameters in 
the main model to: 
- Age (< 60 and ≥ 60) 
- PaO2/FiO2 ratio (≤ 100 and > 100) 
- SAPS3 (< 50 and ≥ 50) 
- Duration of symptoms at randomization, days (≤ 7 and > 7) 
- Duration of moderate / severe ARDS to randomization, hours (≤ 24 hours and > 24 hours to 48 
hours)  
- Position at randomization; (prone or supine) 
- HScore(30) (≥ 169 and < 169) 
- Use of corticosteroids before randomization 
- Use of vasopressors at randomization 
 
We will perform the following pre-specified sensitivity analysis: patients with laboratory confirmed 
COVID-19, patients with laboratory confirmed and probable COVID-19, per-protocol analysis (patients 
that received the proposed treatment in the intervention group and patients that not received 
corticosteroids in the control group) and an as-treated analysis (considering patients which received any 
dose of corticosteroids in the control group). 
 
Future additions  
We plan to collect blood samples for transcriptomic studies after randomization and after 10 days to 
evaluate if the treatment effect of dexamethasone changes based on the genetic expression of leukocytes 
and to follow patients for a period of 12 months in order to perform future analyses on clinical outcomes 
and quality of life.   
 
Trial organization 
The Steering Committee is constituted by the study investigators of the Coalition COVID-19 Brazil 
III and will be responsible for the development of the study protocol, manuscript drafts and study 
submission to publication. All other study committees will report to the Steering Committee.  
The Trial Management Committee (TMC) is formed by members of the Coalition COVID-19 Brazil 
III and is responsible for:  

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i. Conduction of the study: creating the electronic case report forms (eCRF), designing the 
investigator manual and the operations manuals, managing and controlling data quality. 
ii. Research center management: selecting and training the research centers, assisting the center in 
regulatory issues, monitoring recruitment rates, monitoring follow-up, sending study materials 
to research centers. 
iii. Statistical analysis and reporting: completing the statistical analyses and helping to write the 
final manuscript. 
The Adjudication Committee is responsible for evaluating all laboratory negative cases of COVID-
19. Based on the epidemiology, clinical findings and radiological imaging, the committee will classify 
patients as probable or negative cases of COVID-19. 
The Data Monitoring Committee is composed by an external statistician and experts in critical care 
medicine independent of the study’s investigators (see supplementary material - Appendix 4 for further 
information). The DMC will be responsible for the interim analysis and will provide guidance to the 
Steering Committee regarding the continuation and safety of the trial after the interim analyses based on 
the evidence of significant differences between intervention or control group regarding ventilator free 
days at day 28, mortality or adverse events. 
 
Ethical considerations and dissemination 
The trial was designed according to the guidelines for good clinical practice and followed the 
principles of the Declaration of Helsinki and was approved by the Brazilian National Committee of 
Ethics in Research (Comissão Nacional de Ética em Pesquisa - CONEP). All protocol amendments 
must be approved by CONEP before its implementation. 
Given the growing number of COVID-19 cases in Brazil, most hospitals have adopted total 
restriction policies in ICU visitation in order to contain viral spreading. Also, we expect that virtually 
none of the patients will be able to give consent due to their clinical condition. Therefore, the CONEP 
allowed for different approaches in obtaining the consent from the patients’ legal representatives, such 
as consent by email or any other digital format and by voice or video. Patients will be included in the 
study only after the Informed Consent Form is obtained by the study’s investigators. Patients and their 
legal representatives can withdrawal from the study at any time and for any reason. Patients’ next of kin 
are assured that this withdrawal will not have any impact regarding the patients’ care. Before withdrawal 
patients or their legal representative will be asked if data can continue to be collected, despite receiving 
the study interventions. Patients who withdrawal consent from the study will not be replaced by other 
participants.  
The study will be submitted for publication after completion irrespective of its findings. The 
manuscript elaboration will be an inalienable responsibility of the Steering Committee. The main paper 
will be authored by the steering committee members plus the principal investigators of the 10-top 
enrolling sites, which can contribute intellectually to the manuscript. 

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DISCUSSION 
 
This is the first randomized controlled trial evaluating the efficacy of early dexamethasone 
administration in moderate and severe ARDS caused by the SARS-CoV2 virus. Corticosteroids have 
been used in ARDS treatment for almost 50 years.(31) However, there is still controversy around the 
efficacy of this treatment. The literature suggests a potential benefit of early administration in more 
severe cases with a possible influence on the outcome depending on the ARDS cause (bacterial versus 
viral pneumonia, primary vs. secondary ARDS). Also, most of the published data is from small, 
retrospective studies in heterogeneous populations.  
The most common adverse effects of corticosteroids use is hyperglycemia, but as shown in a recent 
trial,(9) patients receiving dexamethasone had a similar frequency of hyperglycemia (76%) as compared 
to controls (70%). Also, the trial showed no difference in new infections in the ICU between groups.  
Our trial has significant strengths compared to the published literature. The study population will be 
homogenous comprising only critically ill patients with moderate or severe ARDS. We offer a precise 
and reproducible intervention protocol and we will include patients in the early phase of ARDS. Early 
ARDS phase probably coincides with a later phase in the disease process, which might reduce the risk of 
increased viral replication induced by the study drug as suggested by previous authors for MERS 
virus(11) and SARS-CoV1 infection.(10)  
We acknowledge our trial has some limitations. It is an open-label trial, which can interfere in the use 
of other immunomodulatory therapies such as the use of convalescent plasma, tocilizumab or 
hydroxychloroquine, especially in the control group. However, we choose an objective primary outcome 
with clear definitions, which reduces the influence of the open label nature in the outcome assessment. 
If we confirm our hypothesis of benefit of using dexamethasone in ARDS due to SARS-CoV2 
infection, the consequences for public health will be enormous, especially considering the COVID-19 
pandemic. Given the unprecedented impact in global health and the lack of ICU beds in most countries 
during the pandemic, an increase in days alive and free of mechanical ventilation should help unburden 
the health care systems worldwide and will represent a noteworthy improvement in ARDS treatment. 
 
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11. Arabi YM, Mandourah Y, Al-Hameed F, Sindi AA, 
Almekhlafi GA, Hussein MA, Jose J, Pinto R, Al-Omari 
A, Kharaba A, Almotairi A, Al Khatib K, Alraddadi B, 
Shalhoub S, Abdulmomen A, Qushmaq I, Mady A, 
Solaiman O, Al-Aithan AM, Al-Raddadi R, Ragab A, 
Balkhy HH, Al Harthy A, Deeb AM, Al Mutairi H, Al-
Dawood A, Merson L, Hayden FG, Fowler RA; Saudi 
Critical Care Trial Group. Corticosteroid therapy for 
critically ill patients with middle east respiratory 
syndrome. Am J Respir Crit Care Med. 2018;197(6):757-
67.  
12. Ni YN, Chen G, Sun J, Liang BM, Liang ZA. The effect 
of corticosteroids on mortality of patients with influenza 
pneumonia: a systematic review and meta-analysis. Crit 
Care. 2019;23(1):99.  
13. Bhimraj A, Morgan RL, Shumaker AH, Lavergne V, 
Baden L, Cheng VC, et al. Infectious Diseases Society of 
America Guidelines on the Treatment and Management 
of Patients with COVID-19. Clin Infect Dis. 2020 Apr 
27; ciaa478. Online ahead of print.  
14. The Australian and New Zealand Intensive Care Society 
ANZICS). COVID-19 Guidelines. Version 1. [cited 2020 
May 10]. Available from: https://www.anzics.com.au/wp-
content/uploads/2020/03/ANZICS-COVID-19-
Guidelines-Version-1.pdf  
15. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall 
RS, Manson JJ; HLH Across Speciality Collaboration, 
UK. COVID-19: consider cytokine storm syndromes and 
immunosuppression. Lancet. 2020;395(10229):1033-4. 
16. Ramos-Casals M, Brito-Zerón P, López-Guillermo A, 
Khamashta MA, Bosch X. Adult haemophagocytic 
syndrome. Lancet. 2014;383(9927):1503-16.  
17. Chan AW, Tetzlaff JM, Altman DG, Laupacis A, 
Gøtzsche PC, Krleža-Jerić K, et al. SPIRIT 2013 
statement: defining standard protocol items for clinical 
trials. Ann Intern Med. 2013;158(3):200-7.  
18. Béduneau G, Pham T, Schortgen F, Piquilloud L, 
Zogheib E, Jonas M, Grelon F, Runge I, Nicolas Terzi, 
Grangé S, Barberet G, Guitard PG, Frat JP, Constan A, 
Chretien JM, Mancebo J, Mercat A, Richard JM, 
Brochard L; WIND (Weaning according to a New 
Definition) Study Group and the REVA (Réseau 
Européen de Recherche en Ventilation Artificielle) 
Network 
‡. Epidemiology 
of 
Weaning 
Outcome 
according to a New Definition. The WIND Study. Am J 
Respir Crit Care Med. 2017;195(6):772-83.  
19. Ministério da Saúde. Protocolo de Manejo Clínico para o 
Novo Coronavírus (2019-nCoV). Brasília: Ministério da 
Saúde; 2020. [citado 2020 Mar 28]. Disponível em: 
https://portalarquivos2.saude.gov.br/images/pdf/2020/fev
ereiro/11/protocolo-manejo-coronavirus.pdf  
20. ARDS Definition Task Force; Ranieri VM, Rubenfeld 
GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, et 
al. Acute respiratory distress syndrome: the Berlin 
Definition. JAMA. 2012;307(23):2526-33.  
21. Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al. 
Correlation of chest CT and RT-PCR testing in 
coronavirus disease 2019 (COVID-19) in China: a report 
of 1014 cases. Radiology. 2020 Feb 26:200642. Online 
ahead o print. 
22. Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, 
O'Neil L, McLeod L, Delacqua G, Delacqua F, Kirby J, 
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Consortium. 
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Inform. 
2019;95:103208.  
23. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, 
Conde JG. Research electronic data capture (REDCap)--a 
metadata-driven methodology and workflow process for 
providing translational research informatics support. J 
Biomed Inform. 2009;42(2):377-81. 
24. Writing Group for the Alveolar Recruitment for Acute 
Respiratory 
Distress 
Syndrome 
Trial 
(ART) 
Investigators; Cavalcanti AB, Suzumura EA, Laranjeira 
LN, Paisani DM, Damiani LP, Guimarães HP, et al. 
Effect of lung recruitment and titrated positive end-
expiratory pressure (PEEP) vs low PEEP on mortality in 
patients with acute respiratory distress syndrome: a 
randomized clinical trial. JAMA. 2017;318(14):1335-45. 
25. Lehmann EL. Nonparametrics: statistical methods based 
on ranks. Holden-Day; 1975. 
26. Rice TW, Wheeler AP, Thompson BT, deBoisblanc BP, 
Steingrub J, Rock P; NIH NHLBI Acute Respiratory 
Distress Syndrome Network of Investigators. Enteral 
omega-3 
fatty 
acid, 
gamma-linolenic 
acid, 
and 
antioxidant supplementation in acute lung injury. JAMA. 
2011;306(14):1574-81.  
27. Hodgson CL, Cooper DJ, Arabi Y, King V, Bersten A, 
Bihari S, et al. Maximal Recruitment Open Lung 
Ventilation in Acute Respiratory Distress Syndrome 
(PHARLAP). A Phase II, Multicenter Randomized 
Controlled Clinical Trial. Am J Respir Crit Care Med. 
2019;200(11):1363-72.  
28. Blenkinsop A, Parmar MK, Choodari-Oskooei B. 
Assessing the impact of efficacy stopping rules on the 
error rates under the multi-arm multi-stage framework. 
Clin Trials. 2019;16(2):132-41.  
29. R Foundation for Statistical Computing. R: A language 
and environment for statistical computing [program]. 
Vienna, Austria: R Foundation for Statistical Computing; 
2019. 
30. Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, 
Chahwan D, et al. Development and validation of the 
HScore, 
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hemophagocytic 
syndrome. 
Arthritis 
Rheumatol. 
2014;66(9):2613-20. 
31. McConn R, Del Guercio LR. Respiratory function of 
blood in the acutely ill patient and the effect of steroids. 
Ann Surg. 1971;174(3):436-50. 
 

COVID-19-associated ARDS treated with DEXamethasone 
 
13 
Rev Bras Ter Intensiva. 2020 
 
 
 
 
 
 
 
 
Table 2 - Berlin Criteria for ARDS diagnosis 
Timing 
Within one week of a known clinical insult or new or worsening respiratory symptoms 
Chest imaging 
Bilateral opacities – not fully explained by effusions, lobar/lung collapse, or nodules 
Origin of edema 
Respiratory failure not fully explained by cardiac failure or fluid overload 
Oxygenation 
 
Moderate 
100mmHg < PaO2/FiO2 ≤ 200mmHg with PEEP ≥ 5cmH2O 
Severe 
PaO2/FiO2 ≤ 100mmHg with PEEP ≥ 5cmH2O 
PaO2/FiO2 - partial pressure of oxygen/fraction of inspired oxygen; PEEP - positive end-expiratory pressure.  
 
 
Table 3 - HScore for diagnosis of secondary hemophagocytic lymphohistiocytosis 
 
Variable 
Number of points 
Temperature (°C) 
 
< 38.4 
0 
38.4 to 39.4 
33 
>39.4 
49 
Organomegaly 
 
No 
0 
Spleen or liver 
23 
Spleen AND liver 
38 
Number of cytopenia 
 
1 lineage 
0 
2 lineages 
24 
3 lineages 
34 
Triglyceride (mg/dL) 
 
< 133 
0 
133 to 354 
44 
> 354 
64 
Fibrinogen (g/dL) 
 
> 2.5 
0 
< 2.5 
30 
Ferritin 
 
< 2000 
0 
2000 to 6000 
35 
> 6000 
50 
Aspartate transaminase (AST) (U/L) 
 
< 30 
0 
≥ 30 
19 
Hemophagocytosis features on bone marrow aspirate 
 
No 
0 
Yes 
35 
Known immunosuppression  
 
No 
0 
Yes 
18 
Table 1 - The 6-point Ordinal Scale 
1 
Not hospitalized. 
2 
Hospitalized, not requiring supplemental oxygen. 
3 
Hospitalized, requiring supplemental oxygen. 
4 
Hospitalized, requiring non-invasive ventilation or nasal high-flow oxygen therapy  
5 
Hospitalized, requiring invasive mechanical ventilation or ECMO 
6 
Death 
ECMO - extracorporeal membrane oxygenation. 
 
 

COVID-19-associated ARDS treated with DEXamethasone 
 
Rev Bras Ter Intensiva. 2020 
 
 
   Figure 1 - Study diagram. ARDS - acute respiratory distress syndrome; ICU - intensive care unit. 
 
 
 
 
                                Figure 2 - Study timeline. ICU - intensive care unit; MV - mechanical ventilation. 
 
 
  SUPPLEMENTARY MATERIAL 

COVID-19-associated ARDS treated with DEXamethasone 
 
Rev Bras Ter Intensiva. 2020 
 
 
Appendix 1 - SPIRIT 2013 checklist 
Section/item 
Item 
Description 
Page 
Administrative information 
Title 
1 
Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym 
1 
Trial registration 
2a 
Trial identifier and registry name. If not yet registered, name of intended registry 
4 
2b 
All items from the World Health Organization Trial Registration Data Set 
4 
Protocol version 
3 
Date and version identifier 
6 
Funding 
4 
Sources and types of financial, material, and other support 
1 
Roles and responsibilities 
5a 
Names, affiliations, and roles of protocol contributors 
1,33 
5b 
Name and contact information for the trial sponsor 
1 
 
5c 
Role of study sponsor and funders, if any, in study design; collection, management, analysis, and interpretation of data; 
writing of the report; and the decision to submit the report for publication, including whether they will have ultimate 
authority over any of these activities 
1 
 
5d 
Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication committee, 
data management team, and other individuals or groups overseeing the trial, if applicable (see Item 21a for data 
monitoring committee) 
16,17 
Introduction 
 
 
 
Background and rationale 
6a 
Description of research question and justification for undertaking the trial, including summary of relevant studies 
(published and unpublished) examining benefits and harms for each intervention 
5,6 
 
6b 
Explanation for choice of comparators 
5 
Objectives 
7 
Specific objectives or hypotheses 
6,7 
Trial design 
8 
Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group), allocation ratio, 
and framework (eg, superiority, equivalence, noninferiority, exploratory) 
6,9 
Methods: participants, interventions, and outcomes 
 
Study setting 
9 
Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be collected. 
Reference to where list of study sites can be obtained 
6 
Eligibility criteria 
10 
Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will 
perform the interventions (eg, surgeons, psychotherapists) 
7,8,9 
Interventions 
11a 
Interventions for each group with sufficient detail to allow replication, including how and when they will be administered 
10 
11b 
Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose change in 
response to harms, participant request, or improving/worsening disease) 
11,12 
11c 
Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence (eg, drug tablet 
return, laboratory tests) 
10,11,16,17 
11d 
Relevant concomitant care and interventions that are permitted or prohibited during the trial 
10,11,12 
Outcomes 
12 
Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood pressure), 
analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, median, proportion), 
and time point for each outcome. Explanation of the clinical relevance of chosen efficacy and harm outcomes is strongly 
recommended 
6,7,13 

COVID-19-associated ARDS treated with DEXamethasone 
 
Rev Bras Ter Intensiva. 2020 
 
Participant timeline 
13 
Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. 
A schematic diagram is highly recommended (see Figure) 
Figure 1 
Sample size 
14 
Estimated number of participants needed to achieve study objectives and how it was determined, including clinical and 
statistical assumptions supporting any sample size calculations 
13,14 
Recruitment 
15 
Strategies for achieving adequate participant enrolment to reach target sample size 
7,8,9 
Methods: Assignment of interventions (for controlled trials) 
 
Allocation 
 
 
 
Sequence generation 
16a 
Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for 
stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be 
provided in a separate document that is unavailable to those who enrol participants or assign interventions 
9 
Allocation concealment 
mechanism 
16b 
Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed 
envelopes), describing any steps to conceal the sequence until interventions are assigned 
9 
Implementation 
16c 
Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions 
9,10 
Blinding (masking) 
17a 
Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data 
analysts), and how 
10 
 
17b 
If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s allocated 
intervention during the trial 
N/A 
Methods: Data collection, management, and analysis 
 
Data collection methods 
18a 
Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to 
promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, 
questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection 
forms can be found, if not in the protocol 
12,13,16,17 
 
18b 
Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for 
participants who discontinue or deviate from intervention protocols 
12,13,16,17 
Data management 
19 
Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double 
data entry; range checks for data values). Reference to where details of data management procedures can be found, if not 
in the protocol 
12,13,16,17 
Statistical methods 
20a 
Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical 
analysis plan can be found, if not in the protocol 
14,15 
 
20b 
Methods for any additional analyses (eg, subgroup and adjusted analyses) 
15,16 
 
20c 
Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical 
methods to handle missing data (eg, multiple imputation) 
14,15,16 
Methods: Monitoring 
 
Data monitoring 
21a 
Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is 
independent from the sponsor and competing interests; and reference to where further details about its charter can be 
found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed 
16,17 
 
21b 
Description of any interim analyses and stopping guidelines, including who will have access to these interim results and 
make the final decision to terminate the trial 
14 
Harms 
22 
Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other 
unintended effects of trial interventions or trial conduct 
11 
Auditing 
23 
Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from 
investigators and the sponsor 
NA 
Ethics and dissemination 
 

COVID-19-associated ARDS treated with DEXamethasone 
 
Rev Bras Ter Intensiva. 2020 
 
Research ethics approval 
24 
Plans for seeking research ethics committee/institutional review board (REC/IRB) approval 
17,18 
Protocol amendments 
25 
Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes, analyses) to 
relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, regulators) 
17,18 
Consent or assent 
26a 
Who will obtain informed consent or assent from potential trial participants or authorized surrogates, and how (see Item 
32) 
17 
 
26b 
Additional consent provisions for collection and use of participant data and biological specimens in ancillary studies, if 
applicable 
NA 
Confidentiality 
27 
How personal information about potential and enrolled participants will be collected, shared, and maintained in order to 
protect confidentiality before, during, and after the trial 
12,13 
Declaration of interests 
28 
Financial and other competing interests for principal investigators for the overall trial and each study site 
19 
Access to data 
29 
Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that limit such 
access for investigators 
13 
Ancillary and post-trial care 
30 
Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial participation 
NA 
Dissemination policy 
31a 
Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals, the public, and 
other relevant groups (eg, via publication, reporting in results databases, or other data sharing arrangements), including 
any publication restrictions 
17,18 
 
31b 
Authorship eligibility guidelines and any intended use of professional writers 
18 
 
31c 
Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code 
13,17,18 
Appendices 
 
 
 
Informed consent materials 
32 
Model consent form and other related documentation given to participants and authorised surrogates 
NA, per 
Brazilian law 
Biological specimens 
33 
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in the 
current trial and for future use in ancillary studies, if applicable 
NA 
 
 

COVID-19-associated ARDS treated with DEXamethasone 
 
Rev Bras Ter Intensiva. 2020 
Appendix 2 - Steering committee 
 
 
COALITION COVID-19 Brazil III Investigators 
 
Bruno Martins Tomazini, Israel Silva Maia, Eduardo Leite Vieira Costa, Alexandre Biasi Cavalcanti, Regis 
Goulart Rosa, Álvaro Avezum, Viviane Cordeiro Veiga, Renato Delascio Lopes, Lucas Petri Damiani, Flávia 
Ribeiro Machado, Otavio Berwanger, Luciano César Pontes de Azevedo for the COALITION COVID-19 Brazil 
III Investigators. 
 
 
 
Appendix 3 - Statistical Analysis Plan (SAP) Version 2.0 
 
 
Sample size and power 
There is a lack of reliable data available in patients with ARDS due to COVID-19 to allow an accurate sample 
size calculation. We therefore used data from a randomized controlled trial in non-COVID-19 ARDS patients1, a 
well-designed multicenter trial that is representative of ARDS outcomes in Brazil, to calculate  the sample size. It 
was assumed a mean of ventilator-free days (VFD) at 28 days of 8 days ± 9 days (standard deviation) in the control 
group. With a two-sided type I error of 0.05 and power of 80% to identify a difference in three days free of 
mechanical ventilation between groups, a sample size of 290 patients would be needed. However, in the end of 
May 2020, before the first interim analysis, after discussing the protocol with the Data Monitoring Committee 
(DMC), the Steering Committee decided to increase the sample size based on the following rational: Given the 
uncertainty regarding the normality of distribution of VFD, based on the Pitman Asymptotic Relative Efficiency2, 
the sample size should be increased by 15% to preserve study power coupled with a 4% increase considering 
possible lost to follow-up  and withdrawal of consent. Therefore, a final sample size of 350 patients is needed. 
Also, due to the lack of data about ventilator free days in COVID-19 patients, the sample size will be updated 
using the pooled standard deviation of ventilator free days of the first interim analysis, unless by the time of the 
first interim analysis all patients have been recruited.  
The minimal clinically important difference of three days for VFD was chosen based on other trials3 4 along 
with what is perceived as a significant improvement to the in-hospital complications, costs, and intensive care unit 
availability, especially in countries with limited resources. 
 
Interim analysis 
Two interim analyses are planned for safety and efficacy evaluation, after 96 patients and 234 patients with the 
complete follow up to the primary outcome. Since the recruitment rate for the study is expected to increase giving 
the increase in number of cases of COVID-19 in Brazil it is possible that by the time all the patients for the second 
interim analysis have completed the follow-up for the primary outcome, the entire sample has already been 
recruited. Therefore, in this specific situation, the second interim analysis will be cancelled.  
We will use the Haybittle–Peto boundary stopping rule for both safety and efficacy based on the evidence of 
significant differences between intervention or control group regarding ventilator free days at day 28, mortality or 
adverse events. The stopping rule for safety will be a p-value <0.01 and for efficacy p-value <0.001. The 
Haybittle–Peto boundary is a conservative stopping rule at interim analysis that has minimal impact in increasing 
type I error in two-arm trials5. We will not adjust the final tests for sequential analysis. The interim analyses will 
be performed by an external and independent DMC. 
 
Basic reporting principles: 
The baseline characteristics of the patients will be displayed as the supplementary table 1 (Table 1S): 
 
 
 
 
 

COVID-19-associated ARDS treated with DEXamethasone 
 
Rev Bras Ter Intensiva. 2020 
 
Table 1S - Baseline characteristics of included patients 
 
 
Dexamethasone 
(Dex.) 
Control 
(Cont.) 
n = xxx 
n = xxx 
Age, mean (SD) 
xx.x ± xx.x 
xx.x ± xx.x 
Female sex, N (%) 
xx.x (xx.x) 
xx.x (xx.x) 
SAPS3 score, mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
Number of non-pulmonary organ failures, median [IQR] 
x.xx [x.xx - x.xx] 
x.xx [x.xx - x.xx] 
Time since onset of symptoms, median [IQR], days 
x.xx [x.xx - x.xx] 
x.xx [x.xx - x.xx] 
Days intubated prior to randomization, median [IQR] 
x.xx [x.xx - x.xx] 
x.xx [x.xx - x.xx] 
COVID-19, N (%) 
   Positive 
xx.x (xx.x) 
xx.x (xx.x) 
   Negative 
xx.x (xx.x) 
xx.x (xx.x) 
   In analysis 
xx.x (xx.x) 
xx.x (xx.x) 
   Not collected/unavailable 
xx.x (xx.x) 
xx.x (xx.x) 
Comorbidities, N (%) 
   Hypertension 
xx.x (xx.x) 
xx.x (xx.x) 
   Diabetes 
xx.x (xx.x) 
xx.x (xx.x) 
   Former smoker 
xx.x (xx.x) 
xx.x (xx.x) 
   Active smoker 
xx.x (xx.x) 
xx.x (xx.x) 
   Obesity 
xx.x (xx.x) 
xx.x (xx.x) 
   Solid tumor 
xx.x (xx.x) 
xx.x (xx.x) 
   Hematologic malignancy 
xx.x (xx.x) 
xx.x (xx.x) 
   Heart failure 
xx.x (xx.x) 
xx.x (xx.x) 
   COPD 
xx.x (xx.x) 
xx.x (xx.x) 
   AIDS 
xx.x (xx.x) 
xx.x (xx.x) 
   Chronic renal failure 
xx.x (xx.x) 
xx.x (xx.x) 
   Chronic dialysis 
xx.x (xx.x) 
xx.x (xx.x) 
   Cirrhosis 
xx.x (xx.x) 
xx.x (xx.x) 
   Asthma 
xx.x (xx.x) 
xx.x (xx.x) 
   Neuromuscular disease 
xx.x (xx.x) 
xx.x (xx.x) 
   Previous MI 
xx.x (xx.x) 
xx.x (xx.x) 
Clinical characteristics 
   Systolic BP, mmHg, mean (SD) 
xx.x ± xx.x 
xx.x ± xx.x 
   Diastolic BP, mmHg, mean (SD) 
xx.x ± xx.x 
xx.x ± xx.x 
   HR, bpm, mean (SD) 
xx.x ± xx.x 
xx.x ± xx.x 
   SpO2, %, mean (SD) 
xx.x ± xx.x 
xx.x ± xx.x 
   HScore ≥169, N0 (%) 
xx.x (xx.x) 
xx.x (xx.x) 
Respiratory measures (mean, SD) 
   PaO2/FiO2 
xx.x ± xx.x 
xx.x ± xx.x 
   Tidal volume, mL/kg predicted body weight 
xx.x ± xx.x 
xx.x ± xx.x 
   Plateau airway pressure (cmH2O) 
xx.x ± xx.x 
xx.x ± xx.x 
   Minute ventilation, L/min 
xx.x ± xx.x 
xx.x ± xx.x 
   Respiratory rate, breaths/min 
xx.x ± xx.x 
xx.x ± xx.x 
   Driving pressure, cmH2O 
xx.x ± xx.x 
xx.x ± xx.x 
   Positive end expiratory pressure, cmH2O 
xx.x ± xx.x 
xx.x ± xx.x 
   Respiratory system static compliance, ml/cmH2O      
xx.x ± xx.x 
xx.x ± xx.x 
Intravenous sedation, N (%) 
xx.x (xx.x) 
xx.x (xx.x) 
Richmond Agitation Sedation Scale, median [IQR] 
x.xx [x.xx - x.xx] 
x.xx [x.xx - x.xx] 
Treatment during study period, N (%) 
   Vasopressors 
xx.x (xx.x) 
xx.x (xx.x) 
   Renal replacement therapy 
xx.x (xx.x) 
xx.x (xx.x) 
   Use of neuromuscular blocking agents 
xx.x (xx.x) 
xx.x (xx.x) 
   ECMO 
xx.x (xx.x) 
xx.x (xx.x) 

COVID-19-associated ARDS treated with DEXamethasone 
 
Rev Bras Ter Intensiva. 2020 
 
   Prone position 
xx.x (xx.x) 
xx.x (xx.x) 
Blood Sample  
 
 
   Creatinine, mg/dL, mean (SD) 
xx.x ± xx.x 
xx.x ± xx.x 
   D-dimer, ng/dL, mean (SD) 
xx.x ± xx.x 
xx.x ± xx.x 
   Hemoglobin, g/dL, mean (SD) 
xx.x ± xx.x 
xx.x ± xx.x 
   Total leucocyte count, µg/mL, median [IQR] 
x.xx [x.xx - x.xx] 
x.xx [x.xx - x.xx] 
   Platelets, /mm3, mean (SD) 
xx.x ± xx.x 
xx.x ± xx.x 
   Lymphocytes, µg/mL, median [IQR] 
x.xx [x.xx - x.xx] 
x.xx [x.xx - x.xx] 
   Lactate (mg/dL) 
xx.x ± xx.x 
xx.x ± xx.x 
   Troponin, median [IQR] 
x.xx [x.xx - x.xx] 
x.xx [x.xx - x.xx] 
Additional Medication, N (%) 
 
 
   Hydroxychloroquine 
xx.x (xx.x) 
xx.x (xx.x) 
   Azithromycin 
xx.x (xx.x) 
xx.x (xx.x) 
   Other antibiotics 
xx.x (xx.x) 
xx.x (xx.x) 
   Oseltamivir 
xx.x (xx.x) 
xx.x (xx.x) 
   Lopinavir+Ritonavir 
xx.x (xx.x) 
xx.x (xx.x) 
Use of corticosteroids before randomization, N0(%) 
xx.x (xx.x) 
xx.x (xx.x) 
 
 
The main analysis study population will comprise all patients who have been randomized (intention-to-treat 
population), using the group allocated as variable, regardless of the medication administered.  
The primary objective is to evaluate the effectiveness of early intravenous (IV) dexamethasone administration 
in ventilator-free days at 28 days after randomization, defined as alive and free from mechanical ventilation in 
adult patients with moderate or severe ARDS due to confirmed or probable SARS-CoV2 infection. Patients 
discharged from the hospital alive before 28 days will be considered alive and free from mechanical ventilation at 
day 28. Number of days free from mechanical ventilation will be presented as mean and standard deviation. The 
treatment effect will be presented as mean difference, with 95% confidence interval and P-value. We will use a 
generalized linear model with beta-binomial distribution or zero/one inflated beta distribution, with center as 
random effect and adjusted for age, corticosteroid use before randomization and PaO2/FiO2 ratio.  
All-cause mortality rates at 28 days will be analyzed using a mixed Cox model, with centers as random effects 
(frailty model). The treatment effect on SOFA Score 48h, 72h, and 7 days after randomization will be analyzed by 
a linear mixed model with centers as random effects. For the clinical status of patients, an ordinal logistic 
regression will be used. The results will be presented as a proportional odds ratio comparing two combinations: 
Intervention versus Control. The probability ratios will be derived from a mixed logistic regression of proportional 
probabilities adjusted for age and PaO2/FiO2 ratio, with random intercepts for the center. The cumulative ordinal 
scores will be presented separately, as well as the main secondary results. Each odds ratio will be estimated using 
mixed logistic regression. The same models will be used to compare the effects of treatment on the follow-up. In 
case of the proportional odds assumption is not met, categories of the Ordinal scale 1-4 will be grouped as a single 
category for the analysis. All secondary outcomes are exploratory and no adjustment for multiple testing will be 
made. 
Adverse events will be expressed as counts and percentages and compared between groups using the Chi-
square test. The main results will be displayed as the supplementary table 2 (Table 2S). The significance level for 
all analyses will be 0.05. There will be no adjustment for multiple testing. All analyses will be performed using the 
R software6 (R Core Team, Vienna, Austria, 2020). 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 2S - Main results presentation 
 
Outcomes 
 
Dex. 
 
Cont. 
Treatment effect 
Dex. versus Cont. 
n = xxx 
n = xxx 
[IC95%] 
p valor 
Primary outcome 
 
 
 
 
  Ventilator free days from 1 to 28 d, mean (SD) 
xx.x ± xx.x 
xx.x ± xx.x 
x.xx [x.xx; x.xx] 
x.xx 
Secondary outcomes 
 
 
Clinical status at day 15, N (%) 
 
 
 
 
   Category 1 - 5 versus 6 (alive vs dead) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
   Category 1 - 4 versus 5 - 6 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
   Category 1 - 3 versus 4 - 6 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
   Category 1 - 2 versus 3 - 6 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
   Category 1 versus 2 to 6 (at home versus hospital or dead) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
All-cause mortality at 28 days 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
Number of days of MV from 1 to 28 d 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
ICU free days at 28 days 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
SOFA scores 
 
 
   48 hours 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
   72 hours 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
   7 days 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
Adverse events 
 
 
 
 
New diagnosis of infection until day 28, N (%) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
Insulin use for hyperglycemia, N (%) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
 
Sensitivity analyses 
We plan to perform analyses to assess treatment effects on the primary and secondary outcomes considering 
only patients that received the proposed treatment in the intervention group and patients that not received 
corticosteroids in the control group (per protocol analysis). Additionally, we will also perform sensitivity analysis 
for the primary outcome in the following groups: 
1. Confirmed COVID-19 infection 
2. Confirmed and probable COVID-19 infection 
3. Patients which received corticosteroids and patients which did not received corticosteroids (as treated 
analysis) 
4. Patients which received the proposed treatment in the intervention group and patients that not received 
corticosteroids in the control group (Per protocol analysis) 
 
Subgroup analyses 
Will also perform subgroup analysis adding an interaction parameter with group in the main model for (Table 
3S): 
1. Age, years (< 60 and ≥ 60) 
2. PaO2/FiO2 ratio, mmHg (≤ 100 and >100) 
3. SAPS3, points (< 50 and ≥ 50) 
4. Duration of symptoms at randomization, days (≤ 7 and > 7) 
5. Duration of moderate / severe ARDS to randomization, hours (≤ 24 hours and > 24 hours to 48 hours)  
6. Position at randomization; (prone or supine) 
7. HScore (≥ 169 and < 169) 
8. Use of corticosteroids before randomization 
9. Use of vasopressors at randomization 
 
Finally, the ordinal score (secondary outcome) will be available daily for each patient up to 15 days. 
These results will be presented in an alluvial graph for each arm. The conditional probabilities of change in stages 
(1 to 6) will be estimated via Bayesian Networks to better describe the time when the intervention can change the 
distribution of the score or estimate the probability of discharge. For example, Bayesian networks allow estimating 
the probability of discharge on day 6 if the patient is without oxygenation support on day 5. We plan to present this 
independent manuscript analysis with and report transition probabilities and relative risk (with confidence intervals 
obtained through bootstrap techniques) for relevant scenarios. 
 
 

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Table 3S - Effect of dexamethasone vs control on ventilator free days according to subgroups 
 
Subgroups 
Dex. 
 
Cont. 
Treatment Effect 
Dex. versus Cont. 
n = xxx 
n = xxx 
HR [IC95%] 
p valor 
Age 
 
 
 
 
   < 60 years 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
   ≥ 60 years 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
PaO2/FiO2 
 
 
 
 
   ≤ 100mmHg 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
   > 100mmHg 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
SAPS 3 
 
 
   < 50 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
   ≥ 50 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
Duration of symptoms at randomization, d 
 
 
 
 
   ≤ 7 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
   > 7  
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
Duration of moderate / severe ARDS to randomization, h  
 
 
 
 
≤ 24 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
> 24 to 48 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
Position at randomization 
 
 
   Supine 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
   Prone 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
HScore  
 
 
   < 169 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
   ≥ 169 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
Use of corticosteroids before randomization 
 
 
 
 
  Yes 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
   No 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
Use of vasopressors at randomization 
 
 
 
 
  Yes 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
   No 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx [x.xx; x.xx] 
x.xx 
 
 
Treatment adherence report 
Patients in the intervention group should receive the intervention for 10 days or until ICU discharge, whichever 
comes first and patients in the control group should not receive corticosteroids. However, since it is an open label 
study, it is possible that deviations in the protocol happen. Thus, we will describe the use of study drug in all arms 
and use of corticosteroids in the control group until the 10th day.  
 
 
 
REFERENCES 
1.  Writing Group for the Alveolar Recruitment for Acute 
Respiratory 
Distress 
Syndrome 
Trial 
(ART) 
Investigators; Cavalcanti AB, Suzumura EA, Laranjeira 
LN, Paisani DM, Damiani LP, Guimarães HP, et al. 
Effect of lung recruitment and titrated positive end-
expiratory pressure (PEEP) vs low PEEP on mortality in 
patients with acute respiratory distress syndrome: a 
randomized clinical trial. JAMA. 2017;318(14):1335-45. 
2. Lehmann EL. Nonparametrics: statistical methods based 
on ranks. Holden-Day; 1975. 
3. Rice TW, Wheeler AP, Thompson BT, deBoisblanc BP, 
Steingrub J, Rock P; NIH NHLBI Acute Respiratory 
Distress Syndrome Network of Investigators. Enteral 
omega-3 
fatty 
acid, 
gamma-linolenic 
acid, 
and 
antioxidant supplementation in acute lung injury. JAMA. 
2011;306(14):1574-81.  
4. Hodgson CL, Cooper DJ, Arabi Y, King V, Bersten A, 
Bihari S, et al. Maximal Recruitment Open Lung 
Ventilation in Acute Respiratory Distress Syndrome 
(PHARLAP). A Phase II, Multicenter Randomized 
Controlled Clinical Trial. Am J Respir Crit Care Med. 
2019;200(11):1363-72. 
5. Blenkinsop A, Parmar MK, Choodari-Oskooei B. 
Assessing the impact of efficacy stopping rules on the 
error rates under the multi-arm multi-stage framework. 
Clin Trials. 2019;16(2):132-41.  
6. R Foundation for Statistical Computing. R: A language 
and environment for statistical computing [program]. 
Vienna, Austria: R Foundation for Statistical Computing; 
2019. 

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Appendix 4 - Data Monitoring Committee (DMC) Charter Version 1.1. June 10th, 2020 
 
Content 
Charter details 
Introduction 
Name of the trial 
COVID-19-associated ARDS treated with DEXamethasone: CoDEX Trial 
Trial Intervention 
Intravenous dexamethasone 
Objectives 
Primary objective 
1. Evaluate the effectiveness of early intravenous (IV) dexamethasone administration in ventilator-free days at 28 days after 
randomization in adult patients with moderate or severe ARDS due to confirmed or probable SARS-CoV2 infection 
Secondary objectives 
1. All-cause mortality rates at 28 days after randomization 
2. Clinical status of patients at 15 days after randomization using the 6-point Ordinal Scale 
3. Number of days of mechanical ventilation from randomization to day 28 
4. ICU free days at day 28 
5. Change in the Sequential Organ Failure Assessment (SOFA) Score 48h, 72h and 7 days after randomization 
Outline of scope of charter 
The purpose of this document is to describe the membership, terms of reference, roles, responsibilities, authority, decision-
making of the DMC for the CoDEX Trial, including the timing of meetings, methods of providing information to and from the 
DMC, frequency and format of meetings, statistical issues and relationships with other committees 
Roles and responsabilities 
A broad statement of the aims of the 
committee 
To protect and serve the CoDEX Trial patients regarding safety and to assist and advise the Academic Steering Committee to 
protect the validity and credibility of the CoDEX Trial. 
To safeguard the interests of the CoDEX Trial participants, assess the safety and efficacy of the interventions during the trial, 
and monitor the overall conduct of the CoDEX Trial. 
Terms of reference 
The DMC should receive and review the progress and accruing data of the CoDEX Trial and provide advice on the conduct of 
the trial to the Academic Steering Committee. 
The DMC should inform the Academic Steering Committee if, in their view: 
I.The results are likely to convince a broad range of clinicians, including those supporting the trial and the general clinical 
community, that one trial arm, or a subset of trial population, is clearly indicated or contraindicated, and there was a 
reasonable expectation that this new evidence would materially influence patient management. 
Specific roles of DMC 
The DMC will assess and provide recommendations on the study protocol, DMC Charter, Statistical analysis plan and 
collected data and safety. 
The DMC will review the trial data after 96 patients and 234 of patients with complete follow up to the primary outcome. The 
review of the trial’s progress will include data quality, and main endpoints (ventilator free days at 28 days and all-cause 
mortality at 28 days), including safety data. 
Before or early in the trial 
Whether the DMC will have input into the 
protocol 
All potential DMC members should have sight of the protocol before agreeing to join the committee. Before recruitment 
begins the trial will have undergone review by the sponsor, scrutiny by other trial committees, a research ethics committee 
(REC), Medicines and Healthcare products Regulatory Agency (MHRA) and Health Research Authority. Therefore, if a potential 
DMC member has major reservations about the trial, they should report these to the Academic Steering Committee and may 
decide not to accept the invitation to join. DMC members should be independent and constructively critical of the ongoing 
trial, but also supportive of aims and methods of the trial. 
Whether the DMC will meet before the 
start of the trial 
The DMC will meet early in the course of the trial, to discuss the protocol, the trial, any analysis plan, future meetings, and to 
have the opportunity to clarify any aspects with the Academic Steering Committee.  
Any issues specific to the disease under 
study 
Issues specific to the disease under study should be described. 
Any specific regulatory issues 
The DMC should be aware of any regulatory implications when making recommendations.   
Any other issues specific to the treatment 
under study 
Issues specific to the treatment under study should be described.   
Whether members of the DMC will have 
a contract 
DMC members do not formally sign a contract but formally register their assent to join the group by confirming (1) that they 
agree to be on the DMC and (2) that they agree with the contents of this Charter.  Any competing interests should be declared 
at the same time. Members should complete and return the agreement and potential competing interests form.  
Composition 
Membership and size of the DMC 
Membership will consist of three members, which include at least one clinician experienced in the clinical area and at least 
one experienced clinical statistician. Additional members experienced in clinical trials should reflect the other specialities 
involved in the trial. The DMC will be formed only by overseas members. 
The members should not be involved with the trial in any other way nor have competing interests that could impact on the 
trial. Any competing interests, both real and potential, must be declared.  Although members may be able to act objectively 
despite such connections, complete disclosure enhances credibility. A short competing interest form should be completed and 
returned by the DMC members to the trial coordinating team (agreement and potential competing interests form).   
The members of the IDMC for this trial are:  
(1) Professor Carol Hodgson (Chair) 

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(2) Professor Michael Bailey (Statistician) 
(3) Professor Theodore Iwashyna 
The Chair, how they are chosen and the 
Chair’s role 
The Chair should have previous experience of serving on DMCs and experience of chairing meetings and be able to facilitate 
and summarize discussions. The Chair will be chosen by the Academic Steering Committee and will be responsible for 
choosing the other two DMC members. The Chair is expected to facilitate and summarize discussions and keep copies of all 
reports and communications. 
Other Chair’s roles are: 
1. Hold all DMC meetings and ensure that all relevant data is reviewed 
2. Ensure that only DMC members are present during the analysis and deliberation of the DMC data 
3. Approve written minutes of all closed sessions of the DMC meetings 
4. Create and archive written minutes of all executive sessions of DMC meetings. These minutes will remain confidential 
only to DMC members until after the database has been blocked and the sponsor's disclosure. 
5. Arrange additional consultations with subject matter experts as needed. 
The 
responsibilities 
of 
the 
DMC 
statistician 
The DMC statistician will be chosen by the DMC Chair and will provide independent statistical expertise. 
The statistician appointed by the DMC Chair will perform independent statistical analyses and have unlimited access to the 
entire study database. However, the analysis plan of the independent statistician of the DMC should follow the same principles 
described in the statistical analysis plan of the study. 
The responsibilities of the Steering 
Committee 
The responsibilities of the Academic Steering Committee are: 
1.  Monitor the conduct of the study, as well as the collection and quality of the study data 
2.  Review scheduled DMC reports, with aggregated hidden data (i.e. all subjects, not separated by treatment group) 
3.  Provide joint review and approval of minutes of open and final sessions of the DMC data review meetings 
4.  Accept or reject DMC recommendations. The DMC shall be notified in writing of the response to any recommendations, 
including the reasoning in which the recommendations are not accepted 
5.  Communicate the recommendations of the DMC for changes in the conduct of the study to the researchers, who in turn 
communicate them to the Ethics Committees of each site and to the National Council of Ethics in Research (CONEP) and 
to the National Health Surveillance Agency (ANVISA). Communication on the DMC with researchers will be limited to 
formal requests for changes in the conduct of the study and will not include information on the conduct of DMC 
meetings 
6.  The implementation of changes to the protocol is in accordance with the DMC recommendations. 
Relationships 
Role of the funding source 
The COVID-19 Brazil Coalition III is a partnership of academic leaders who designed a study initiated by a double-sponsored 
researcher, the Coalition in conjunction with Aché Pharmaceuticals which provided the study drug, the drug logistics 
distribution to the study centres and insurance for the study patients. However, Aché will have no participation or interfere with 
the trial design, enrolment, analysis, manuscript writing, or publication, it will have no role in the DMC´s choices, in 
appointing members, or in the design of this regulation. The decision to interrupt or continue the trial on the recommendation 
of the DMC will be entirely the responsibility of the Academic Steering Committee, without influence or supervision of the 
Aché. However, Aché will be notified of any decision of the steering committee as soon as the decision is made. 
Payments to DMC members 
Each DMC member will receive a payment of US$ 1000 (One thousand United States Dollars).   
DMC members should not use interim results to inform trading in pharmaceutical shares, and careful consideration should be 
given to trading in stock of companies with competing products. 
Organization of DMC meetings 
Expected frequency of DMC meetings 
DMC members will meet once at the beginning of the study, at each interim analysis and whenever they deem it necessary or 
at the request of the Academic Steering committee, especially when new evidence emerges about the therapy being studied or 
when adverse events are reported. 
Whether meetings will be face-to-face or 
by teleconference 
All meetings will be held by videoconference. 
How DMC meetings will be organized, 
especially regarding open and closed 
sessions, including who will be present 
in each session 
The meetings will consist of open and closed parties. During the initial open part of the meeting, a steering committee 
member will conduct a brief presentation related to the status of the trial, its conduct, and any concerns, and will be available 
for questions from DMC members. The closed session, which will take place immediately after, and will be attended only by 
DMC members. 
Trial documentation and procedures to ensure confidentiality and proper communication 
Confidentiality 
regarding 
trial’s 
information 
To protect the scientific integrity of the study under review, all members of the DMC agree to keep all information in absolute 
secrecy and will not disclose data, findings, or decisions outside the scope of communication defined in this Charter. 
Materials provided to DMC for analysis are highly confidential and should not be disclosed in any way to unauthorized third 
parties. 
Will the IDMC be blinded to the 
treatment allocation 
The DMC will not be blinded to the treatment allocation. 
To whom the DMC will communicate the 
decisions/ recommendations that are 
reached 
DMC recommendations duly voted and approved are transmitted in writing or by teleconference from the President of the 
DMC to the Academic Steering committee expeditiously, at the latest within the established deadline. 
 
Proposal of the statistical analysis plan 
General principles and interim analyses 
There will be two pre-planned interim analyses for safety and efficacy evaluation, after 96 patients and 234 of patients with the 
complete follow up to the primary outcome. Since the recruitment rate for the study is expected to increase giving the increase 

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in number of cases of COVID-19 in Brazil it is possible that by the time all the patients for the second interim analysis had 
completed the follow-up for the primary outcome, the entire sample has already been recruited. Therefore, in this specific 
situation, the second interim analysis will be cancelled. 
We will use the Haybittle–Peto boundary stopping rule for both safety and efficacy based on the evidence of significant 
differences between intervention or control group regarding ventilator free days at day 28, mortality or adverse events. The 
stopping rule for safety will be a p-value <0.01 and for efficacy p-value <0.001. The Haybittle–Peto boundary is a conservative 
stopping rule at interim analysis that has minimal impact in increasing type I error in two-arm trials. 
Primary outcome analysis and All-cause 
mortality analysis 
The locking of the database will be performed after obtaining 28 days of follow-up of all patients and all the necessary actions 
to obtain follow-up are performed. The main analysis will be made considering the intention to treat principle. 
The primary outcome is to evaluate the effectiveness of early intravenous (IV) dexamethasone administration in ventilator-free 
days at 28 days after randomization, defined as alive and free from mechanical ventilation in adult patients with moderate or 
severe ARDS due to confirmed or probable SARS-CoV2 infection. Patients discharged from the hospital alive before 28 days 
will be considered alive and free from mechanical ventilation at day 28. Number of days free from mechanical ventilation will 
be presented as mean and standard deviation. The treatment effect will be presented as mean difference, with 95% confidence 
interval and P-value. We will use a generalized linear model with beta-binomial distribution or zero/one inflated beta 
distribution, with center as random effect and adjusted for age, corticosteroid use before randomization and PaO2/FiO2 ratio. 
All-cause mortality rates at 28 days will be analyzed using a mixed Cox model, with centers as random effects (frailty model). 
Safety and stopping standards 
If there is a general increase in severe adverse events at 28 days with a two-tailed alpha threshold <0.01, the DMC will 
consider efficacy data together with safety information to consider stopping the study, also the DMC can choose to wait for the 
next interim analysis for weighting. To do this, the DMC will have access to the entire study database required for this specific 
intermediate analysis and may request additional data if necessary. If the study is not interrupted after any intermediate 
analysis, the alpha thresholds for severe adverse events will not be adjusted in the final statistical analysis. The occurrence of 
other non-severe adverse events (hyperglycemia) will also be weighted by DMC. 
Additionally, the DMC will consider other factors outside the rigid limits mentioned above to prepare a recommendation on the 
study. Safety and efficacy findings often need to be weighed along with external evidence outside the rigid limits. We believe 
that the DMC is free to carry out such consideration and provide its opinion in these terms. 
Decision making 
What decisions/recommendations will be 
open to the DMC 
DMC will recommend one of the following written actions to the Academic Steering Committee: 
1. Continue the study according to the protocol and any related changes 
2. Modify the study protocol. Modifications may include, but are not with others, changes in inclusion/exclusion criteria, 
frequency of safety monitoring, changes in study procedures 
3. Pause inclusion, with pending resolution of a specified problem 
4. Interrupt the study 
How decisions or recommendations will 
be reached within the DMC 
DMC members formally vote on all recommendations to be submitted to the steering committee. To vote, a Member of the 
DMC must be present at the meetings convened. A simple majority vote of the members transmits a proposal, motion or 
recommendation to the Academic Steering Committee. 
Reporting 
To whom will the DMC report their 
recommendations / decisions, and in 
what form 
The DMC will report their recommendations/decisions to the Academic Steering Committee through a letter or e-mail within 
one week after the DMC meeting. A copy of the DMC recommendation will be stored in the trial master file. 
 

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Agreement and potential competing interests form 
 
COVID-19-associated ARDS treated with DEXamethasone: CoDEX Trial 
 
 
Please complete the following document and return to the CoDEX Trial Coordinator. 
 
 
 
I have read and understood the DMC Charter version 1.1, dated June 10th, 2020. 
 
I agree to join the DMC for this trial 
 
I agree to treat all sensitive trial data and discussions confidentially 
 
 
The avoidance of any perception that members of a DMC may be biased in some fashion is 
important for the credibility of the decisions made by the DMC and for the integrity of the trial. 
Possible competing interest should be disclosed to the trial Steering Committee. In many cases 
simple disclosure up front should be sufficient.  Otherwise, the (potential) DMC member should 
remove the conflict or stop participating in the DMC.  
 
 
 
No, I have no competing interests to declare. 
 
Yes, I have competing interests to declare (please detail below). 
 
 
Please provide details of any competing interests: 
 
 
 
 
 
 
 
Name: ___________________________ 
 
Signed: __________________________ 
  Date: ______________