ABSTRACT
Mesenchymal stromal cells (MSC) have immunomodulatory and tissue-regenerative properties and have shown promising results in acute respiratory distress syndrome (ARDS) of multiple causes, including COVID-19. We conducted a randomised (1:1), placebo-controlled, double-blind clinical trial to assess the efficacy and safety of one bone marrow-derived MSC infusion in patients with moderate to severe ARDS caused by COVID-19. The primary endpoint was change in the PaO2/FiO2 ratio from baseline to day 7. Key secondary endpoints included clinical improvement in the WHO 7-point ordinal scale and safety variables. Twenty patients were included. Clinical improvement at day 7 was greater in the MSC group than in the control (5, 50% vs 0, 0%). Median time to discontinuation of supplemental oxygen was also shorter (14 [IQR 10-18] vs. 23 [IQR 19.5-25] days), resulting in shorter hospital length of stay (17.5 [IQR 11-28] vs. 28 [IQR 26-28] days). PaO2/FiO2 increase from baseline to day 7 was 83.3 in the MSC group vs. 57.6 in the control group. No infusion-related or treatment-related serious adverse events occurred during the one-year follow-up. MSC therapy is safe in moderate to severe COVID-19 ARDS and may be beneficial, even in a context of low mortality, accelerating clinical recovery and hospital discharge. Trial Registration EudraCT Number: 2020-002193-27, registered on July 14th, 2020, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-002193-27/ES. NCT number: NCT04615429, registered on November 4th, 2020, https://clinicaltrials.gov/ct2/show/NCT04615429.
Subject(s)
COVID-19 , Respiratory Distress SyndromeABSTRACT
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.
Subject(s)
COVID-19 , Respiratory Tract Infections , ConvalescenceABSTRACT
Background: Passive immunotherapy with convalescent plasma (CP) is a potential treatment for COVID-19 for which evidence from controlled clinical trials is lacking. Methods: We conducted a multi-center, randomized clinical trial in patients hospitalized for COVID-19. All patients received standard of care treatment, including off-label use of marketed medicines, and were randomized 1:1 to receive one dose (250-300 mL) of CP from donors with IgG anti-SARS-CoV-2. The primary endpoint was the proportion of patients in categories 5, 6 or 7 of the COVID-19 ordinal scale at day 15. Results: The trial was stopped after first interim analysis due to the fall in recruitment related to pandemic control. With 81 patients randomized, there were no patients progressing to mechanical ventilation or death among the 38 patients assigned to receive plasma (0%) versus 6 out of 43 patients (14%) progressing in control arm. Mortality rates were 0% vs 9.3% at days 15 and 29 for the active and control groups, respectively (log-rank p=0.056). No significant differences were found in secondary endpoints. At inclusion, patients had a median time of 8 days (IQR, 6-9) of symptoms and 49,4% of them were positive for anti-SARS-CoV-2 IgG antibodies. Conclusions: Convalescent plasma could be superior to standard of care in avoiding progression to mechanical ventilation or death in hospitalized patients with COVID-19. The strong dependence of results on a limited number of events in the control group prevents drawing firm conclusions about CP efficacy from this trial. (Funded by Instituto de Salud Carlos III; NCT04345523).
Subject(s)
COVID-19 , DeathABSTRACT
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.