Single-Arm, Open-Label Phase 2 Trial of Preemptive Methylprednisolone to Avert Progression to Respiratory Failure in High-Risk Patients with COVID-19

INTRODUCTION: Covid-19 is a triphasic disorder first typified by a viral phase that lasts from the first onset of symptoms until seven days later. This is followed by a second and third phase, initially characterized by the appearance of lung infiltrates, followed in 20% by respiratory failure. The second phase is usually heralded by an elevation of serologic inflammatory markers including CRP, ferritin, IL-6, LDH as well as D-dimers. Approximately 20% proceed to the second phase and are usually then treated with dexamethasone, provided they are oxygen-dependent since these are the only cases that benefit from dexamethasone. If we had objective criteria to predict this 20% that develop severe illness, they could preemptively be treated with steroids. In this exploratory study we investigated the early use of preemptive steroids in the setting of early disease, in high-risk non-oxygen dependent cases. METHODS: Eligible patients were those 21 years or older with a diagnosis of Covid-19 and oxygen saturation ≥91%. For patients to be classified as high-risk, they had to exhibit two or more of the following abnormalities 7-10 days after first symptom: IL-6 ≥ 10 pg/ml, ferritin > 500 ng/ml, D-dimer > 1 mg/L (1,000 ng/ml), CRP > 10 mg/dL (100 mg/L), LDH above normal range lymphopenia (absolute lymphocyte count <1,000 /μL), oxygen saturation between 91-94%, or CT chest with evidence of ground glass infiltrates. Primary endpoint was progression to respiratory failure. CALL score method was used to predict the expected number of cases of respiratory failure. High risk patients received methylprednisolone (MPS) 80 mg IV daily x 5 days starting no earlier than seven days from first onset of symptoms. The primary endpoint was progression to hypoxemic respiratory failure defined as PaO2 <60 mm Hg or oxygen saturation ≤90%. Secondary endpoints included survival at 28 days from registration, admission to intensive care and live discharge from the hospital. Change in levels of inflammatory markers and length of hospitalization were also assessed. RESULTS: In 76 patients, the expected number with respiratory failure was 30 (39.5%), yet only 4 (5.3%) developed that complication (p=.00001). Survival at 28 days was 98.6%. Improvement in inflammatory markers correlated with favorable outcome. CONCLUSIONS: Our results are encouraging and suggest that this approach is both effective and safe.