DEXamethasone EARLY Administration in Hospitalized Patients With Covid-19 Pneumonia (EARLYDEXCoV2)

DEXamethasone EARLY Administration in Hospitalized Patients With Covid-19 Pneumonia and High Risk of Developing Acute Respiratory Distress Syndrome

Fundación para la Investigación e Innovación Biomédica del Hospital Universitario Infanta Leonor, Kern Pharma, S.L.

The aim of this study is to evaluate the efficacy of dexamethasone in hospitalized adults with COVID-19 pneumonia who do not require supplementary oxygen on admission, but have high risk of developing acute respiratory distress syndrome (ARDS). This is a prospective, multicenter, phase 4, parallel-group, randomized and controlled trial that is open-label to investigators, participants and clinical outcome assessors. Eligible participants include adults (age 18 years or older), diagnosed with SARS-CoV-2 infection, evidence of infiltrates on chest radiography or computerized tomography, peripheral capillary oxygen saturation ≥94% and 22 breaths per minute breathing room air, and high risk of developing ARDS defined by a lactate dehydrogenase higher than 245 U/L, C-Reactive Protein higher than 100 mg/L, and absolute lymphocytes lower than 800 cells/µL. Eligible participants will meet two of the three before analytical criteria associated with severe COVID-19. Patients will provide written informed consent. Exclusion criteria include patients with a history of allergy to dexamethasone, pregnant or lactating women, oral or inhaled corticosteroids treatment within 15 days before randomization, immunosuppressive agent or cytotoxic drug therapy within 30 days before randomization, neutropenia <1000 cells/µL, human immunodeficiency virus infection with CD4 cell counts <500 cells within 90 days after randomization, dementia, chronic liver disease defined by ALT or AST ≥5 times the upper limit of normal, chronic kidney injury defined by a glomerular filtration rate ≤30 ml/min, hemodialysis or peritoneal dialysis, uncontrolled infection, and patients who are already enrolled in another clinical trial. Study participants will be randomized in a 1:1 ratio to receive dexamethasone base 6 mg once daily for seven days or standard of care. The primary endpoint is to prevent of development of moderate ARDS. Based on the Berlin criteria, moderate ARDS is defined by a PaO2/FiO2 ratio >100 mmHg and ≤200 mmHg. Study participants will be randomized in a 1:1 ratio to receive dexamethasone versus standard of care using a randomization platform. Included participants will be hospitalized at the time of randomization. The study will be undertaken at Infanta Leonor-Virgen de la Torre University Hospital, Enfermera Isabel Zendal Emergency Hospital, and Infanta Cristina Hospital, Madrid, Spain.

Coronavirus disease 2019 (COVID-19) can lead to acute respiratory distress syndrome (ARDS), severe hypoxic respiratory failure and, death. It has been reported that the mechanism of COVID-19 is related to cytokine storms and subsequent immunogenic damage, especially lung damage. Dexamethasone, with immunomodulatory properties, decrease mortality in critically ill patients with COVID-19. However, the benefits in patients without hypoxia remain unknown. We hypothesize that early administration of dexamethasone in hospitalized adult patients with COVID-19 pneumonia without hypoxia on admission, but risk factors for developing ARDS might prevent severe acute respiratory failure and death. The investigators designed a multicenter prospective phase 3 parallel-group randomized and controlled trial. It is planned to recruit 126 hospitalized adults patients with COVID-19 pneumonia without hypoxia on admission, but at high risk of developing ARDS, admitted to the emergency room or internal medicine wards. One enrolled, the participants will be randomised to receive oral or intravenous dexamethasone base at a dose of 6 mg once daily for 7 days or standard of care once enrolled. The primary outcome is the development of moderate-severe ARDS in patients with COVID-19 pneumonia without hypoxia on admission, but at high risk of disease progression. Based on the Berlin criteria, moderate ARDS is defined by a PaO2/FiO2 ratio >100 mmHg and ≤200 mmHg. According to The American College of Chest Physicians patients with a PaO2/FiO2 ratio around 200 mmHg requiring supplemental oxygen in nasal cannula at 3 L/min (FiO2 0.30) for a SpO2 of 91-92%. Safety data will be provided. The secondary endpoints are: All-cause mortality for 28 days after randomization, intensive Care Unit (ICU) or Intermediate Respiratory Care Unit (IRCU) transfer for 28 days after randomization, clinical status of the patient using the ordinal scale of the WHO, SOFA on admission, and 4 and 7 days after randomization, hospital length of stay, respiratory support at hospital discharge, and all-cause readmission rate for 3 months after randomization. This trial is considered to be safe. First, dexamethasone has been widely used in clinical practice for decades, and second, patients with greater potential risks of side effects were excluded based on the exclusion criteria. However, adverse events (AE) and serious adverse events (SAE) must be observed and followed in accordance with the good clinical practice guidelines issued by the European Medicine Agency (EMA).AE and SAE will be recorded for 7 days of observation from enrolment. Either may occur during a subject's participation in the research and do not need to have a causal relationship with the treatment. Investigators will evaluate the relationship between the events and the intervention and report it to the ethics committee and data and safety monitoring board. Benefits and potential risks are written in the informed consent document. Patients will be informed about the purpose, interventions, benefits and possible risks of the study. Baseline data including demographic characteristics, assigned group, Sequential Organs Failure Assessment (SOFA) score, the clinical status of the patient using the ordinal scale of the WHO, SpO2, partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio calculated from SpO2/FiO2, blood routine tests, chest radiography, and concomitant drugs will be collected on the first day. General vital signs, changes in the SOFA score, changes in the ordinal scale of the WHO, SpO2, respiratory rate, PaO2/FiO2 ratio, respiratory support, chest radiography, concomitant drugs, adverse event monitoring will be collected on the first day, fourth, seventh, fourteenth day and at discharge. Participants are scheduled for a follow-up visit on the 30 and 90th day to track their long-term prognosis, clinical status and sequelae. Data will be collected from the clinical information system of the hospital. Every participant will be distinguished with a study identifier and initial without full name. An electronic password-protected document containing all the information from the case report format will be set up for statistical analysis. The analysis process will be performed by the primary investigator and designated teammates who are experienced with the trial case report format. The confidentiality and safety of participant's data are guaranteed. Data will be reserved for 25 years for further analysis and investigation in accordance with the European Clinical Trials Directive. We assumed that 30% of participants would meet ARDS, and the use of dexamethasone would reduce this percentage to 15%. This corresponds to a required sample size of 63 per arm, with a 5% two-sided significance level (alpha) and 80% power. The total sample size therefore is planned to be 126. Quantitative variables will be described as the mean with standard deviation when they had a normal distribution, or median and interquartile range (IQR) when they had a non-normal distribution. Qualitative variables were defined by the frequency distribution and percentages. For univariate analysis, the difference in measurement data will be compared between the dexamethasone and standard care groups using Student's t -test or the Mann-Whitney U, and qualitative variables will be compared using Chi-squared test and Fisher's exact test depending on the normality of the variable. Kaplan-Meier analysis will be used to show the effect of dexamethasone on patient survival probability. A p-value of less than 0.05 will be considered statistically significant. Results will be obtained using Statistical Package for the Social Sciences software, version 26.0. Results will be submitted for publication in peer-reviewed journals.

COVID-19 pneumonia, Acute respiratory distress syndrome, Prevention, Randomised controlled trial, Dexamethasone

This is a prospective, multicentre, phase 3, parallel-group, randomized and controlled trial that is open-label to investigators, participants and clinical outcome assessors

The study participants and the clinicians who will evaluate post-treatment outcomes will be known to group assignment. The clinical research team will not be blinded to group assignment

Based on the Berlin criteria, moderate ARDS is defined by a PaO2/FiO2 ratio >100 mmHg and ≤200 mmHg. According to The American College of Chest Physicians patients with a PaO2/FiO2 ratio around 200 mmHg requiring supplemental oxygen in nasal cannula at 3 L/min (FiO2 0.30) for a SpO2 of 91-92%. The collected data as outcome measure will be general vital sign, Sequential Organ Failure Assessment (SOFA) score, the clinical status of the patient using the ordinal scale of the WHO, SpO2, partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio calculated from SpO2/FiO2, blood routine tests and chest radiography. Concomitant drugs and adverse event monitoring will be collected. Data will measure during admission. Participants will schedule for a follow-up visit on the 30 and 90th day to track their long-term prognosis, clinical status and sequelae.

Intensive Care Unit (ICU) or Intermediate Respiratory Care Unit (IRCU) transfer for 28 days after randomization

Intensive Care Unit (ICU) or Intermediate Respiratory Care Unit (IRCU) transfer for 28 days after randomization

The World Health Organization COVID-19 ordinal scale represents intensity of medical intervention, with higher scores for interventions more burdensome for the patient, and highest score for death. Minimum value = 1, and maximum value = 8

The Sequential Organ Failure Assessment score is a simple and objective score that allows for calculation of both the number and the severity of organ dysfunction in six organ systems (respiratory, coagulatory, liver, cardiovascular, renal, and neurologic). The SOFA score can be used to determine level of organ dysfunction and mortality risk. Higher scores for interventions more burdensome for the patient, and highest score for death. Minimum value = 0, and maximum value = 24

Hospital length of stay in days. From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 90 days.

Inclusion Criteria: Adults (age 18 years or older). Diagnosed with SARS-CoV-2 infection by Polymerase Chain Reaction or rapid antigen test on upper respiratory tract (nasopharyngeal and oropharyngeal) specimens. Evidence of infiltrates on chest radiography or computerized tomography. Peripheral capillary oxygen saturation (SpO2) ≥94% and <22 breaths per minute (bpm) breathing room air. High risk of developing ARDS defined by a lactate dehydrogenase higher than 245 U/L, C-Reactive Protein higher than 100 mg/L, and absolute lymphocytes lower than 800 cells/µL. Eligible participants will meet two of the three before analytical criteria associated with severe COVID-19. Patients will provide written informed consent or who have a legally authorized representative available to do so. In these exceptional circumstances and following the recommendations of the Spanish Agency of Medicines and Medical Devices, the National Competent Authority of clinical trials, during the coronavirus crisis to avoid the risk of contagion, consent will be possible to obtained orally in the presence of at least one impartial witness. Exclusion Criteria: Patients with a history of allergy to dexamethasone. Pregnant or lactating women. Oral or inhaled corticosteroids treatment within 15 days before randomization. Immunosuppressive agent or cytotoxic drug therapy within 30 days before randomization. Neutropenia <1000 cells/µL. Human immunodeficiency virus infection with CD4 cell counts <500 cells within 90 days after randomization. Dementia. Chronic liver disease defined by ALT or AST ≥5 times the upper limit of normal. Chronic kidney injury defined by a glomerular filtration rate ≤30 ml/min, hemodialysis or peritoneal dialysis. Uncontrolled infection. Patients who are already enrolled in another clinical trial.

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