Effectiveness of Glucocorticoid Therapy in Patients with Severe Coronavirus Disease 2019: Protocol of a Randomized Controlled Trial
Coronaviruses are RNA viruses that can infect the respiratory, gastrointestinal, hepatic, and central nervous systems of humans, livestock, avian species, and many mammals. In humans, infection by coronaviruses such as HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1 usually leads to mild, self-limiting upper respiratory tract infections. However, more severe coronaviruses, such as those associated with Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), have caused significant global outbreaks with high mortality rates. In December 2019, a novel coronavirus, designated as 2019-nCoV (later known as SARS-CoV-2), emerged in Wuhan, China, causing Coronavirus Disease 2019 (COVID-19). By February 2020, the virus had spread globally, with tens of thousands of confirmed cases and thousands of deaths.
COVID-19 presents with non-specific symptoms, including fever, cough, myalgia, and diarrhea, with severe cases progressing to respiratory distress, sepsis, and septic shock. During the SARS and MERS outbreaks, systemic glucocorticoids were widely used to manage severe respiratory symptoms, but their effectiveness and safety remain controversial. This study aims to investigate the effectiveness of adjunctive glucocorticoid therapy in patients with severe COVID-19 through a randomized controlled trial.
Study Design and Methods
This study is an open-labeled, randomized, controlled trial conducted at the Chongqing Public Health Medical Center in China. The trial aims to enroll 48 subjects with severe COVID-19, who will be randomly assigned to either an intervention group or a control group in a 1:1 ratio. The intervention group will receive methylprednisolone via intravenous injection at a dose of 1–2 mg/kg/day for 3 days, while the control group will not receive glucocorticoid therapy. Both groups will receive conventional treatment for COVID-19 as per the guidelines for diagnosis and treatment of COVID-19 (version 6).
The primary endpoint of the study is the change in the Sequential Organ Failure Assessment (SOFA) score at 3 days after randomization. Secondary endpoints include the proportion of mechanical ventilation use at 2 and 4 weeks, mortality at 2 and 4 weeks, duration of hospitalization, and the incidence of adverse events. Subjects will be followed up for 28 days, with visits scheduled at baseline, day 3, day 14, and day 28. During these visits, blood and urine samples will be collected for laboratory testing, including hematologic analysis, urinalysis, clinical chemistry studies, electrolytes, coagulation testing, myocardial enzymes, C-reactive protein, erythrocyte sedimentation rate, procalcitonin, CD4 and CD8 cell counts, blood gas analysis, and 2019-nCoV real-time reverse transcription-polymerase chain reaction (RT-PCR). Chest CT or X-ray will also be performed at each visit.
Ethical Considerations and Data Collection
The study was approved by the Ethics Committee of the Chongqing Public Health Medical Center. Informed consent will be obtained from all participants, and no patient names will appear in any published articles. Data will be collected and entered independently by two researchers to ensure accuracy. Any missing or abnormal data will be verified and explained by the physician. Adverse events (AEs) will be documented, and serious AEs will be reported to the investigators immediately. Short-term glucocorticoid therapy is generally associated with mild side effects, such as hypokalemia, glucose intolerance, hypertension, pancreatitis, and cutaneous, hematologic, immunologic, and neuropsychologic effects, which are reversible upon discontinuation of the drug.
Sample Size and Statistical Analysis
The sample size calculation is based on the primary hypothesis of detecting a 40% reduction in SOFA scores between the treatment and non-treatment groups after 3 days of glucocorticoid therapy. Using PASS software with a power of 80% and a 95% confidence level, the estimated sample size is 24 cases per group, considering a 5% dropout rate. Statistical analysis will be performed using SPSS software. Continuous variables will be described as mean ± standard deviation and analyzed using the t-test for independent samples. Categorical variables will be analyzed using the Chi-squared test or Fisher’s exact test. A p-value of less than 0.05 will be considered statistically significant.
Discussion
The use of systemic glucocorticoids in severe respiratory diseases, including COVID-19, remains controversial. During the SARS outbreak, high-dose glucocorticoids were widely used, with some studies suggesting clinical improvement and reduced cytokine levels, while others indicated increased mortality and delayed viral RNA clearance. Similarly, in MERS patients, glucocorticoid therapy was associated with delayed viral clearance and no significant survival benefit.
In COVID-19, some patients progress to severe Acute Respiratory Distress Syndrome (ARDS), which has a high mortality rate. Glucocorticoids have been used in ARDS management, but their effectiveness is still debated. Some studies suggest that prolonged glucocorticoid treatment can improve clinical outcomes, reduce inflammation, and decrease mechanical ventilation duration, while others report no significant survival benefit or even increased mortality with high-dose glucocorticoids.
This study aims to provide evidence on the effectiveness and safety of mid-dose, short-course glucocorticoid therapy in severe COVID-19 patients. By comparing the clinical outcomes, adverse events, and mortality rates between the intervention and control groups, the study hopes to determine whether systemic glucocorticoids are beneficial in the management of severe COVID-19.
Conclusion
The emergence of COVID-19 has posed significant challenges to global health systems. The role of systemic glucocorticoids in the management of severe COVID-19 remains unclear, and this randomized controlled trial aims to provide much-needed evidence on their effectiveness and safety. The results of this study will help guide clinical decision-making and improve the management of severe COVID-19 patients.
doi.org/10.1097/CM9.0000000000000791
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