Abstract
COVID-19 convalescent plasma (CCP) is a potentially beneficial treatment for COVID-19 that requires rigorous testing. To compile individual patient data from randomized clinical trials of CCP and to monitor the data until completion or until accumulated evidence enables reliable conclusions regarding the clinical outcomes associated with CCP. From May to August 2020, a systematic search was performed for trials of CCP in the literature, clinical trial registry sites, and medRxiv. Domain experts at local, national, and international organizations were consulted regularly. Eligible trials enrolled hospitalized patients with confirmed COVID-19, not receiving mechanical ventilation, and randomized them to CCP or control. The administered CCP was required to have measurable antibodies assessed locally. A minimal data set was submitted regularly via a secure portal, analyzed using a prespecified bayesian statistical plan, and reviewed frequently by a collective data and safety monitoring board. Prespecified coprimary end points-the World Health Organization (WHO) 11-point ordinal scale analyzed using a proportional odds model and a binary indicator of WHO score of 7 or higher capturing the most severe outcomes including mechanical ventilation through death and analyzed using a logistic model-were assessed clinically at 14 days after randomization. Eight international trials collectively enrolled 2369 participants (1138 randomized to control and 1231 randomized to CCP). A total of 2341 participants (median [IQR] age, 60 [50-72] years; 845 women [35.7%]) had primary outcome data as of April 2021. The median (IQR) of the ordinal WHO scale was 3 (3-6); the cumulative OR was 0.94 (95% credible interval [CrI], 0.74-1.19; posterior probability of OR <1 of 71%). A total of 352 patients (15%) had WHO score greater than or equal to 7; the OR was 0.94 (95% CrI, 0.69-1.30; posterior probability of OR <1 of 65%). Adjusted for baseline covariates, the ORs for mortality were 0.88 at day 14 (95% CrI, 0.61-1.26; posterior probability of OR <1 of 77%) and 0.85 at day 28 (95% CrI, 0.62-1.18; posterior probability of OR <1 of 84%). Heterogeneity of treatment effect sizes was observed across an array of baseline characteristics. This meta-analysis found no association of CCP with better clinical outcomes for the typical patient. These findings suggest that real-time individual patient data pooling and meta-analysis during a pandemic are feasible, offering a model for future research and providing a rich data resource.
Highlights
The COVID-19 pandemic has created a humanitarian crisis.[1,2] Identifying safe and effective therapies is challenging given the shifting outbreak locations, disparate efforts to conduct randomized clinical trials (RCTs), and open-label emergency use of treatments.[3,4] Several approaches to hastening progress have been proposed,[5] including launching trials in hot spots, instituting platform designs,[6] and synthesizing data from multiple RCTs
No association of convalescent plasma with clinical outcomes was found. Meaning These findings suggest that real-time individual patient data pooling and meta-analysis during a pandemic are feasible, offering a model for future research and providing a rich data resource
Heterogeneity of treatment effect sizes was observed across an array of baseline characteristics. This meta-analysis found no association of convalescent plasma (CCP) with better clinical outcomes for the typical patient
Summary
The COVID-19 pandemic has created a humanitarian crisis.[1,2] Identifying safe and effective therapies is challenging given the shifting outbreak locations, disparate efforts to conduct randomized clinical trials (RCTs), and open-label emergency use of treatments.[3,4] Several approaches to hastening progress have been proposed,[5] including launching trials in hot spots, instituting platform designs,[6] and synthesizing data from multiple RCTs. Meta-analyses typically pool data from completed RCTs7,8; another approach involves pooling data from trials in various stages, some completed and others continuing enrollment.[9] Because the complexity of the pandemic might be associated with the outcomes of potential therapies, it is essential to analyze individual patient data (IPD) rather than trial summaries.[10] We implemented a practical approach to nearly real-time pooling of IPD from completed and ongoing RCTs11-18 of COVID-19 convalescent plasma (CCP) and report here the results of the COMPILE (COntinuous Monitoring of Pooled International Trials of ConvaLEscent Plasma for COVID-19 Hospitalized Patients) study.[4]
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