Evaluation of Convalescent Plasma Versus Standard of Care for the Treatment of COVID-19 in Hospitalized Patients: study protocol for a phase 2 randomized, open-label, controlled, multicenter trial (preprint)

Background: COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) and causes substantial morbidity and mortality. At the time this clinical trial was planned, there were no available vaccine or therapeutic agents with proven efficacy, but the severity of the condition prompted the use of several pharmacological and non-pharmacological interventions. It has long been hypothesized that the use of convalescent plasma (CP) from infected patients who have developed an effective immune response is likely to be an option for the treatment of patients with a variety of severe acute respiratory infections (SARI) of viral etiology. The aim of this study is to assess the efficacy and safety of convalescent plasma in adult patients with severe COVID-19 pneumonia. Methods: /Design: The ConPlas-19 study is a multicenter, randomized, open-label controlled trial. The study has been planned to include 278 adult patients hospitalized with severe COVID-19 infection not requiring mechanical ventilation (invasive or non-invasive). Subjects are randomly assigned in a 1:1 ratio (139 per treatment arm), stratified by center, to receive intravenously administered CP (single infusion) plus SOC or SOC alone, and are to be followed for 30 days. The primary endpoint of the study is the proportion of patients that progress to categories 5, 6 or 7 (on the 7-point ordinal scale proposed by the WHO) at day 15. Interim analyses for efficacy and/or futility will be conducted once 20%, 40%, and 60% of the planned sample size are enrolled and complete D15 assessment. Discussion: This clinical trial is designed to evaluate the efficacy and safety of passive immunotherapy with convalescent plasma for the treatment of adult patients hospitalized with COVID-19. The results of this study are expected to contribute to establishing the potential place of CP in the therapeutics for a new viral disease. Trial registration: Trial registration at clinicaltrials.gov; Registration Number: NCT04345523; https://clinicaltrials.gov/ct2/show/NCT04345523; Registered on 30 March, 2020. First posted date: April 14, 2020.

COMBINATION OF TOCILIZUMAB AND STEROIDS TO IMPROVE MORTALITY IN PATIENTS WITH SEVERE COVID-19 INFECTION: A SPANISH, MULTICENTER, COHORT STUDY (preprint)

BackgroundWe aimed to determine the impact of tocilizumab use in severe COVID-19 pneumonia mortality. MethodsWe performed a multicentre retrospective cohort study in 18 tertiary hospitals in Spain, from March to April 2020. Consecutive patients admitted with severe COVID-19 treated with tocilizumab were compared to patients not treated with tocilizumab, adjusting by Inverse Probability of the Treatment Weights (IPTW). Tocilizumab effect in patients receiving steroids during the 48h following inclusion was analyzed. ResultsDuring the study period, 506 patients with severe COVID-19 fulfilled inclusion criteria. Among them, 268 were treated with tocilizumab and 238 patients were not. Median time to tocilizumab treatment from onset of symptoms was 11 days (IQR 8-14). Global mortality was 23.7%. Mortality was lower in patients treated with tocilizumab than in controls (16.8% versus 31.5%, HR 0.514 [95CI 0.355-0.744], p< 0.001; weighted HR 0.741 [95CI 0.619-0.887], p = 0.001). Tocilizumab treatment reduced mortality by 14.7% relative to no tocilizumab treatment (RRR 46.7%). We calculated a number necessary to treat of 7. Among patients treated with steroids, mortality was lower in patients treated with tocilizumab than in those treated with steroids alone (10.9% versus 40.2%, HR 0.511 [95CI 0.352-0.741], p = 0.036; weighted HR 0.6 [95CI 0.449-0.804], p< 0.001) (Interaction p = 0.094). ConclusionsThese results show that survival of patients with severe COVID-19 is higher in patients treated with tocilizumab than in those not treated, and that tocilizumab effect adds to that of steroids administered to non-intubated cases with COVID-19 during the first 48 hours of presenting with respiratory failure despite of oxygen therapy. Randomised controlled studies are needed to confirm these results. SummaryWe investigated in-hospital mortality of patients with severe SARS-CoV-2 pneumonia in a multicenter series of patients treated with tocilizumab compared to controls, and adjusted using IPTW. Our results show a beneficial impact of tocilizumab treatment in SARS-CoV-2 pneumonia, that adds to that of steroids.

Evaluation of Convalescent Plasma versus Standard of Care for the Treatment of COVID-19 in Hospitalazed Patients: study protocol for a phase 2 randomized, open-label, controlled, multicenter trial (preprint)

Background: COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) and causes substantial morbidity and mortality. At the time this clinical trial was planned, there were no available vaccine or therapeutic agents with proven efficacy, but the severity of the condition prompted the use of several pharmacological and non-pharmacological interventions. It has long been hypothesized that the use of convalescent plasma (CP) from infected patients who have developed an effective immune response is likely to be an option for the treatment of patients with a variety of severe acute respiratory infections (SARI) of viral etiology. The aim of this study is to assess the efficacy and safety of convalescent plasma in adult patients with severe COVID-19 pneumonia. Methods/Design: The ConPlas-19 study is a multicenter, randomized, open-label controlled trial. The protocol has been prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. The study has been planned to include 278 adult patients hospitalized with severe COVID-19 infection not requiring mechanical ventilation (invasive or non-invasive). Subjects are randomly assigned in a 1:1 ratio (139 per treatment arm), stratified by center, to receive intravenously administered CP (single infusion) plus SOC or SOC alone, and are to be followed for 30 days. The primary endpoint of the study is the proportion of patients that progress to categories 5, 6 or 7 (on the 7-point ordinal scale proposed by the WHO) at day 15. Interim analyses for efficacy and/or futility will be conducted once 20%, 40%, and 60% of the planned sample size are enrolled and complete D15 assessment. Discussion: This clinical trial is designed to evaluate the efficacy and safety of passive immunotherapy with convalescent plasma for the treatment of adult patients hospitalized with COVID-19. The results of this study are expected to contribute to establishing the potential place of CP in the therapeutics for a new viral disease. Trial registration: Trial registration at clinicaltrials.gov; Registration Number: NCT04345523; https://clinicaltrials.gov/ct2/show/NCT04345523; Registered on 30 March, 2020. First posted date: April 14, 2020. Keywords: COVID-19, randomized, controlled trial, protocol, convalescent plasma (CP), antibodies.

IMPACT OF GLUCOCORTICOID TREATMENT IN SARS-COV-2 INFECTION MORTALITY: A RETROSPECTIVE CONTROLLED COHORT STUDY (preprint)

Objective: We aim to determine the impact of steroid use in COVID-19 pneumonia in-hospital mortality. Design: We performed a single-centre retrospective cohort study. Setting: A University hospital in Madrid, Spain, during March 2020. Participants: Patients admitted with SARS-CoV-2 pneumonia. Exposures: Patients treated with steroids were compared to patients not treated with steroids. A propensity-score for steroid treatment was developed. Different steroid regimens were also compared, and adjusted with a second propensity score. Main Outcomes and Measures: To determine the role of steroids in in-hospital mortality, univariable and multivariable analyses were performed, and adjusted including the propensity score as a covariate. Survival times were compared using a log-rank test. Results: During the study period, 463 out of 848 hospitalized patients with COVID19 pneumonia fulfilled inclusion criteria. Among them, 396 (46.7%) consecutive patients were treated with steroids and 67 patients were assigned to the control cohort. Global mortality was 15.1%. Median time to steroid treatment from symptom onset was 10 days (IQR 8 to13). In-hospital mortality was lower in patients treated with steroids than in controls (13.9% [55/396] versus 23.9% [16/67], OR 0.51 [0.27 to 0.96], p= 0.044). Steroid treatment reduced mortality by 41.8% relative to no steroid treatment (RRR 0,42 [0.048 to 0.65). Initial treatment with 1 mg/kg/day of methylprednisolone (or equivalent) versus steroid pulses was not associated with in-hospital mortality (13.5% [42/310] versus 15.1% [13/86], OR 0.880 [0.449-1.726], p=0.710). Conclusions: Our results show that survival of patients with SARS-CoV2 pneumonia is higher in patients treated with glucocorticoids than in those not treated. In-hospital mortality was not different between initial regimens of 1 mg/kg/day of methylprednisolone or equivalent and glucocorticoid pulses. These results support the use of glucocorticoids in SARS-CoV2 infection.