Prospective individual patient data meta-analysis of two randomized trials on convalescent plasma for COVID-19 outpatients
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Abstract
Data on convalescent plasma (CP) treatment in COVID-19 outpatients are scarce. We aimed to assess whether CP administered during the first week of symptoms reduced the disease progression or risk of hospitalization of outpatients. Two multicenter, double-blind randomized trials (NCT04621123, NCT04589949) were merged with data pooling starting when <20% of recruitment target was achieved. A Bayesian-adaptive individual patient data meta-analysis was implemented. Outpatients aged ≥50 years and symptomatic for ≤7days were included. The intervention consisted of 200–300mL of CP with a predefined minimum level of antibodies. Primary endpoints were a 5-point disease severity scale and a composite of hospitalization or death by 28 days. Amongst the 797 patients included, 390 received CP and 392 placebo; they had a median age of 58 years, 1 comorbidity, 5 days symptoms and 93% had negative IgG antibody-test. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The odds ratio (OR) of CP for improved disease severity scale was 0.936 (credible interval (CI) 0.667–1.311); OR for hospitalization or death was 0.919 (CI 0.592–1.416). CP effect on hospital admission or death was largest in patients with ≤5 days of symptoms (OR 0.658, 95%CI 0.394–1.085). CP did not decrease the time to full symptom resolution.
Trial registration: Clinicaltrials.gov NCT04621123 and NCT04589949. Registration: NCT04621123 and NCT04589949 on https://www.clinicaltrials.gov
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SciScore for 10.1101/2021.11.30.21266810: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: Trials had to be approved by the institutional review boards, and competent authorities of the countries involved, and all patients gave written informed consent.
Consent: Trials had to be approved by the institutional review boards, and competent authorities of the countries involved, and all patients gave written informed consent.Sex as a biological variable not detected. Randomization Study patients and selection criteria: Although the exact inclusion and exclusion criteria could vary across the trials, all the subjects had to fulfill the following criteria; 1) Participant of a trial that joined the COMPILEhome consortium, 2) Confirmed COVID-19 diagnosis by a diagnostic PCR or antigen … SciScore for 10.1101/2021.11.30.21266810: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: Trials had to be approved by the institutional review boards, and competent authorities of the countries involved, and all patients gave written informed consent.
Consent: Trials had to be approved by the institutional review boards, and competent authorities of the countries involved, and all patients gave written informed consent.Sex as a biological variable not detected. Randomization Study patients and selection criteria: Although the exact inclusion and exclusion criteria could vary across the trials, all the subjects had to fulfill the following criteria; 1) Participant of a trial that joined the COMPILEhome consortium, 2) Confirmed COVID-19 diagnosis by a diagnostic PCR or antigen test, 3) Neither hospitalized nor at the emergency room department of a hospital before or at the time of randomization, 4) Symptomatic with illness onset ≤7 days at the time of screening for the study, and 5) Age 50 or older. Blinding Overview of Study Design and research partners: Beginning in November 2020, we systematically searched for RCTs recruiting outpatients that compared treatment with CP with a blinded or unblinded control arm in the European (https://www.clinicaltrialsregister.eu/) and American (www.clinicaltrials.gov) trial register. Power Analysis not detected. Table 2: Resources
Antibodies Sentences Resources Pre-planned subgroup analyses assessed the efficacy of the 2 primary outcomes in the following subgroups: 1) days since disease onset (1-5 or >5days), 2) level of neutralizing antibody anti-SARS-CoV-2 titers in transfused plasma and 3) Negative serum anti-SARS-CoV-2 IgG status (Trimeric Spike antibody test, Liaison, Diasorin, Saluggia, Italy). anti-SARS-CoV-2suggested: Noneanti-SARS-CoV-2 IgGsuggested: NoneDiasorin, Saluggia, Italy).suggested: NoneSoftware and Algorithms Sentences Resources Overview of Study Design and research partners: Beginning in November 2020, we systematically searched for RCTs recruiting outpatients that compared treatment with CP with a blinded or unblinded control arm in the European (https://www.clinicaltrialsregister.eu/) and American (www.clinicaltrials.gov) trial register. https://www.clinicaltrialsregister.eu/suggested: (EU Clinical Trials Register, RRID:SCR_005956)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Several limitations should be mentioned. Although we only included patients aged ≥50, and most of them also had comorbidities, the hospital admission rate was relatively low at 9.3%. Therefore, the study was not powered to exclude a small overall treatment effect. However, administering CP to infectious and symptomatic outpatients is complex and labor-intensive. Hence, we think that small CCP’s clinical role is significantly diminished if unable to establish something greater than “a small effect” because it ceases to be practical. As vaccination uptake progressed in patients aged 50 or older and monoclonal antibody-based therapy with proven effectiveness in high-risk outpatients became available, the recruitment dropped dramatically as of June 2021. This resulted in the recommendation by the individual and COMPILEhome DSMBs that further enrollment was unlikely to change the results, and both studies were discontinued. Regarding the advent of the SARS-CoV-2 variants that may be less susceptible to antibodies induced by the original SARS-CoV-2 virus or the alpha variant, it is reassuring that >95% of the patients in both countries were included at a time when the delta variant was still rare (<5%) (Appendix Figure 3 and 4). The last limitation of our study (and all studies on CP for COVID-19 so far) is the lack of a proper phase 2 dose-finding study. In a recent study, we administered 600 mL of CP to 25 SARS-CoV-2 antibody-negative B-cell depleted patients diagnosed with COVID...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04621123 Completed Plasma for Early Treatment in Non-hospitalised Mild or Moder… NCT04589949 Recruiting Early Convalescent Plasma Therapy for High-risk Patients Wit… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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