Justification of the study
Currently, dexamethasone is one of the few drugs that has shown a reduction in mortality in COVID-19 patients [12]. The RECOVERY trial found no benefit in patients with COVID-19 who did not require supplementary oxygen. Unfortunately, the RECOVERY trial did not collect laboratory biomarkers to predict the risk of development of ARDS in these patients. Hence, the need for this study is based on the possibility that the benefit of dexamethasone in this specific subpopulation of patients was underestimated. Our goal in this study is to analyze dexamethasone’s efficacy in preventing the development of ARDS and death in patients with COVID-19 pneumonia who do not require respiratory support, and in whom biomarkers independently associated with increased risk of severe disease are detected.
Study design
Effect of EARLY administration of DEXamethasone in patients with COVID-19 pneumonia without acute hypoxemic respiratory failure, and risk of development of acute respiratory distress syndrome (EARLY-DEX COVID-19) study is a multicenter, randomized, controlled, open-label, parallel-group trial involving 252 hospitalized patients with COVID-19 pneumonia who do not require supplemental oxygen on admission, and laboratory biomarkers related to severe COVID-19 disease are detected. Patients will be randomized and enrolled in Spain. Study sites are listed in Appendix 1.
The trial was designed in accordance with the Declaration of Helsinki [17], the Convention of the European Council related to human rights and biomedicine, and within the requirements established by Spanish legislation in the field of biomedical research, the protection of personal data, and bioethics, which was registered on 8 April 2021 at http://www.clinicaltrials.gov with identification no. NCT04836780. The study protocol (Version 1.2, 17 April 2021) was approved by the Ethics Committee for investigation with medicinal products of the Comunidad de Madrid, Spain, and the institutional review boards of all participating hospitals (Additional file 1). The trial was approved by the Spanish Agency of Drugs and Medical Devices as a clinical randomized study with drugs on 25 May 2021 (Additional file 2 in Spanish).
Prior to any activity carried out as part of the research, subjects will receive a concise and focused presentation of key information about the clinical trial, verbally and with a written consent form. To be included, written informed consent will be requested to patients’ relatives or legal representative by the local investigators. Following the recommendations of the Spanish Agency of Medicines and Medical Devices, during the COVID-19 pandemic, patient consent can be obtained orally and preferably before an impartial witness, documenting it in the patient’s medical records [18]. The forms have been reviewed by the Ethics Committee that authorized the trial.
Our protocol followed the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines [19]. See Additional file 3 for the SPIRIT checklist of the study protocol.
Inclusion criteria
To be eligible for inclusion patients must fulfil the following criteria during screening and prior to enrollment: hospitalized patients aged 18 years or older with confirmed SARS-CoV-2 pneumonia who do not require supplemental oxygen, and risk of developing ARDS. Risk of ARDS is defined by the presence of at least two of the following inflammatory biomarkers: LDH >245 U/L, CRP >100 mg/L, and lymphocyte count <0.80 × 109/L (Table 1).
Table 1
a) Adults (age 18 years or older) |
b) Confirmed COVID-19 based on a positive RT-PCR test or rapid antigen test for SARS-CoV-2 RNA in a respiratory specimen (nasopharyngeal or nasal swab) |
c) Requiring in-hospital care |
d) A chest imaging study compatible with pneumonia (X-ray or computed tomography) |
e) SpO2 ≥94 percent and <22 bpm breathing on room air |
f) The presence of at least two of the following inflammatory biomarkers: • LDH >245 U/L • CRP >100 mg/L • Lymphocyte count <0.80 × 109/L |
Abbreviations: SpO2: Peripheral capillary oxygen saturation; bpm: breaths per minute; LDH: lactate dehydrogenase; CRP: C-Reactive Protein. |
Table 1.
Exclusion criteria
Exclusion criteria include one or more of the following: patients with a history of allergy to corticosteroids, need for supplementary oxygen, pregnancy or breastfeeding status, oral or inhaled corticosteroids treatment in the preceding 15 days, human cytochrome P450 (CYP) enzyme–inhibiting drugs treatment, use of immunosuppressants or immune-modulators (including chemotherapy) in the preceding 30 days, neutropenia <1.0 × 109/L, human immunodeficiency virus infection with CD4 cell counts <0.50 × 109/L in the preceding 90 days, dementia, liver disease defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥5 times the upper limit of normal, chronic kidney disease defined as a glomerular filtration rate ≤30 ml/min, hemodialysis or peritoneal dialysis, uncontrolled infection, and participation in clinical trials of any kind in the previous 28 days.
Randomization
Eligible, consenting patients will be randomly assigned in a 1:1 ratio to receive either dexamethasone plus standard of care (intervention group) or standard of care alone (control group). Dexamethasone will be provided free of charge for this study by the organisation funding. According to the ethical principles for medical research of the Declaration of Helsinki, the use of no placebo (no intervention) is acceptable when no proven intervention exists. The Spanish Agency of Drugs and Medical Devices and the Ethics Committees did not mandate a blinded design or the administration of a placebo. Randomization will be done within the REDCap system with unpredictability of assignments. Local investigators in participating centres are the only authorized personnel to interact with the web-response system through a username and password. Once eligibility is confirmed in the electronic case report form, the treatment group is assigned by the system according to a randomization schedule prepared by a statistician and uploaded as a look-up table to the REDCap system.
Intervention
Patients in the intervention group will receive an intravenous dose of 6 mg once daily from day 1 to day 3, followed by an oral dose of 6 mg once daily from day 4 to day 7 (Figure 1). We selected the same dose as the RECOVERY trial. Participants randomized to the control group will receive standard of care. Given that pulmonary disease can progress rapidly in patients with COVID-19, patients will be closely monitored. For improving intervention adherence, a real-time medication monitoring system will offer monitoring of participants' medication control combined with short message service (SMS) after discharge. Study participants will receive the best standard of care according to the current COVID-19 Treatment Guidelines. Hospitalized patients who do not require supplemental oxygen can receive anticoagulants for prevention of venous thromboembolic disease, gastric ulcer prophylaxis, hydration, antipyretics, antibiotics, and bronchodilators. Although initially the local investigator will assign the patient to the study arm, i.e. corticosteroids, remdesivir, tocilizumab, baricitinib, tofacitinib and sarilumab will be considered in case of a worsening of disease status [10]. All chronic medication prescribed to the patient is permitted to continue at the discretion of the responsible physician/investigator.
For a trial participant, the assigned study intervention will be modified or discontinued by trial investigators if serious adverse events occurring during the study period or withdrawal of participant consent. Regardless of any decision to modify or discontinue their assigned intervention, study participants will be retained in the trial whenever possible to enable follow-up data collection and prevent missing data.
Figure 1. Study design diagram.
Data collection and procedures study
All participating patients, regardless of the study arm into which they are randomized, will be monitored following general standard of care practices. Patients will be assessed once daily by local investigators.
Demographic data including age and sex assigned at birth, comorbidities, and the COVID-19 vaccination status from participants will be collected. Temperature, respiratory rate, cardiac frequency, peripheral capillary oxygen saturation (SpO2), respiratory support, partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2), quick Sequential Organs Failure Assessment (qSOFA) score, and the ordinal scale for clinical improvement of the World Health Organization will be monitored at least once daily. Biochemistry and haematological tests on days 1 and 7, and chest X-ray on days 1, 4, 7 and discharge will be assessed (Table 2). Laboratory determinations will include haemoglobin, white blood cell, lymphocyte count, platelets count, glucose, blood urea nitrogen, serum creatinine, sodium, potassium, LDH, alkaline phosphatase, albumin, ALT, AST, total bilirubin, CRP, prothrombin time, D-dimer, ferritin level, interleukin-6 and procalcitonin. Patients will be followed up to 90 days after randomization.
Table 2
Scheduled protocol activities
| Day 1 | Day 4 | Day 7 | Day of discharge | Day 30 | Day 90 |
Eligibility preliminary assessment | • | | | | | |
Eligibility confirmation | • | | | | | |
Informed consent and enrollment | • | | | | | |
Randomization | • | | | | | |
Intervention | | | |
Demographics data | • | | | | | |
Comorbidities | • | | | | | |
Vital signs | • | • | • | • | | |
SpO2 | • | • | • | • | | |
Respiratory support | • | • | • | • | | |
PaO2/FiO2 | • | • | • | • | | |
qSOFA score | • | • | • | • | | |
Ordinal scale of the WHO | • | • | • | • | | |
Analitycal* | • | | • | | | |
Chest X-ray | • | • | • | • | | |
Concomitant drugs | • | • | • | • | | |
Adverse event monitoring | • | • | • | • | | |
Discharge or death | | | | • | | |
Follow-up | | | | | • | • |
*Hemoglobin, white blood cell, lymphocyte count, platelets count, glucose, blood urea nitrogen, serum creatinine, sodium, potassium, LDH, alkaline phosphatase, albumin, ALT, AST, total bilirubin, CRP, prothrombin time, D-dimer, ferritin level, interleukin-6 and procalcitonin. |
Abbreviations: SpO2: peripheral capillary oxygen saturation; PaO2: partial pressure of arterial oxygen; FiO2: fraction of inspired oxygen; qSOFA: quick Sequential Organs Failure Assessment; WHO: World Health Organization. |
Table 2.
Safety of the intervention will be actively evaluated by daily interrogation of the following common adverse effects of dexamethasone: hyperglycaemia, steroid-induced psychosis, gastrointestinal bleed, new infection, and chorioretinopathy or blurred vision [20].
Primary outcome
The primary outcome is a composite of development of moderate ARDS and all-cause mortality during the 30-day period following enrollment. Based on the Berlin criteria, moderate ARDS is defined by a PaO2/FiO2 >100 mmHg and ≤200 mmHg [21]. Site investigators will be reporting patient status at 30 days, irrespective of whether the patient continues hospitalized, or is discharged home. If patients are discharged alive from the hospital before day 30, the local investigator will contact the patient or relatives by phone to ensure the status of the patient at day 30 after randomization.
Secondary outcomes
Secondary outcomes are:
Local investigators will contact the patient or relatives by phone to ensure the status of the patient at day 90 after randomization. The lead investigator in each site will confirm the recorded 90-day readmission.
The incidence of adverse events and serious adverse events during the study period will be reported.
Results will be communicated at scientific meetings and submitted for publication in peer-reviewed international journals, regardless of the outcome.
Sample size
We powered the study to assess whether the intervention would reduce the incidence of ARDS. Based on a 30% Based on available evidence, we estimate a 30% risk of ARDS in the control group [2]. We assumed that the intervention would reduce ARDS 10%. Assuming 80% power and two-sided alpha =0.05, 226 participants would be needed to detect the resulting reduction of ARDS from 30% in the control group to 20% in the intervention group. We adopted a sample size of 252 (126 per group) to compensate for potential loss to follow-up of some participants.
Statistical analysis
Baseline demographic and clinical characteristics will be presented in both groups. The primary outcome will be calculated for both treatment groups separately with corresponding 95% confidence intervals. Quantitative variables will be defined by mean and standard deviation. Continuous variables will be compared using Student’s t-test (normal distribution) or Mann-Whitney test (non-normal distribution). Qualitative variables will be defined by frequency and compared using Chi-square test or Fisher's exact test. Kaplan-Meier analysis will be used to show the effect of dexamethasone on patient survival probability. The estimates of rate and risk ratios will be adjusted for the age in three categories (<70 years, 70 to 79 years, and ≥80 years). A p-value of less than 0.05 will be considered statistically significant. Statistical analysis will be performed with SPSS V28.0 software (SPSS, Inc. Chicago, Illinois, USA). CONSORT reporting guidelines will be followed to ensure that results are presented in a complete, detailed and systematic way.
Data Management
All participants will be assigned an identification code to ensure the anonymization 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. 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 will not disclose to third persons. In the informed consent form, the participants are informed that their medical records will provide only to the authorized monitors, auditors, or inspectors. Data will be collected in each participating using an electronic case report form (eCRF) within the REDCap system. The investigator is responsible for the data correctness, completeness, and filling in time. Only the principal investigators and the external Data and Safety Monitoring Board will have access to the trial dataset. Medical records of the subjects will be retained in the trial site for 25 years according to the European standards for clinical trials [22].
Safety assessment
All patients who have been randomized and have taken at least one dose of treatment will be analyzed for safety. All adverse events occurring after entry into the study and until hospital discharge will be recorded. An adverse event that meets the criteria for a serious adverse event between study enrollment and hospital discharge will be reported to the local Institutional Review Board. A serious adverse event for this study is any untoward medical occurrence that is believed by the investigators to be causally related to study-drug and results in any of the following: Life-threatening condition, severe or permanent disability, prolonged hospitalization, or a significant hazard as determined by the Data Safety Monitoring Board. Serious adverse events occurring after a participant is discontinued from the study will not be reported unless the investigators feel that the event may have been caused by the study drug.