Randomized Controlled Trial of Early Outpatient COVID-19 Treatment with High-Titer Convalescent Plasma
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Abstract
BACKGROUND
The efficacy of polyclonal high titer convalescent plasma to prevent serious complications of COVID-19 in outpatients with recent onset of illness is uncertain.
METHODS
This multicenter, double-blind randomized controlled trial compared the efficacy and safety of SARS-CoV-2 high titer convalescent plasma to placebo control plasma in symptomatic adults ≥18 years positive for SARS-CoV-2 regardless of risk factors for disease progression or vaccine status. Participants with symptom onset within 8 days were enrolled, then transfused within the subsequent day. The measured primary outcome was COVID-19-related hospitalization within 28 days of plasma transfusion. The enrollment period was June 3, 2020 to October 1, 2021.
RESULTS
A total of 1225 participants were randomized and 1181 transfused. In the pre-specified modified intention-to-treat analysis that excluded those not transfused, the primary endpoint occurred in 37 of 589 (6.3%) who received placebo control plasma and in 17 of 592 (2.9%) participants who received convalescent plasma (relative risk, 0.46; one-sided 95% upper bound confidence interval 0.733; P=0.004) corresponding to a 54% risk reduction. Examination with a model adjusting for covariates related to the outcome did not change the conclusions.
CONCLUSION
Early administration of high titer SARS-CoV-2 convalescent plasma reduced outpatient hospitalizations by more than 50%. High titer convalescent plasma is an effective early outpatient COVID-19 treatment with the advantages of low cost, wide availability, and rapid resilience to variant emergence from viral genetic drift in the face of a changing pandemic.
Trial Registration
ClinicalTrials.gov number, NCT04373460 .
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SciScore for 10.1101/2021.12.10.21267485: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Field Sample Permit: The study was conducted under an FDA Investigational New Drug application sponsored by Johns Hopkins University (IND 19725).
IRB: For the Center for American Indian Health sites, the protocol was also independently reviewed and approved by the Navajo Nation Health Human Research Review Board and the National Indian Health Service IRB.
Consent: All participants provided written informed consent.Sex as a biological variable not detected. Randomization TRIAL DESIGN AND OVERSIGHT: The Convalescent Plasma to Limit SARS-CoV-2 Associated Complications (CSSC-004) Study was a double-blind randomized controlled trial comparing high titer CCP to placebo control plasma. Blinding not … SciScore for 10.1101/2021.12.10.21267485: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Field Sample Permit: The study was conducted under an FDA Investigational New Drug application sponsored by Johns Hopkins University (IND 19725).
IRB: For the Center for American Indian Health sites, the protocol was also independently reviewed and approved by the Navajo Nation Health Human Research Review Board and the National Indian Health Service IRB.
Consent: All participants provided written informed consent.Sex as a biological variable not detected. Randomization TRIAL DESIGN AND OVERSIGHT: The Convalescent Plasma to Limit SARS-CoV-2 Associated Complications (CSSC-004) Study was a double-blind randomized controlled trial comparing high titer CCP to placebo control plasma. Blinding not detected. Power Analysis A sample size of 1280 was determined to have 80% power using a one-sided test to detect at least a 25% reduction in hospital risk and was inflated to 1344 to allow for potential loss to follow-up. Table 2: Resources
Antibodies Sentences Resources Eligible donors were qualified with SARS-CoV-2 antibody (Euroimmun) with minimum titers of ≥1:320 as determined using a validated ELISA assay in a CLIA certified laboratory. SARS-CoV-2suggested: NoneResults 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:In contrast, CCP is available in low- and middle-income countries, has no patent limitations, and is relatively inexpensive to produce, with many single donors being able to provide multiple high titer units, as evident from this trial. Because it provides a diverse mix of antibodies with different specificities and functions, CCP is much less vulnerable to the emergence of antibody resistance In fact, CCP has been used for rescue therapy in immunocompromised patients who developed mAb-resistant SARS-CoV-2 variants5. Since any individual who recovers from variant SARS-CoV-2 mounts antibodies against that variant, CCP is an antibody-based therapy that locally keeps up with variants23. Hence, CCP is likely to remain an important therapeutic option for COVID-19. In our study, the most common reason for hospitalization was symptomatic hypoxia, resulting from pulmonary inflammation in response to SARS-CoV-2 infection. Plasma antibodies mediate several antiviral activities including direct virus neutralization, complement activation, viral particle phagocytosis and antibody-dependent cellular cytotoxicity24. The accumulated COVID-19 vaccine data point to lower antibody levels to prevent severe disease than infection25. Our study faced important challenges. First, standards of care and available therapies changed throughout the study period. Anti-SARS-CoV-2 mAbs became available in late November 2020, which steadily decreased the individuals eligible for CCP. Also, as vaccine utiliz...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04373460 Active, not recruiting Convalescent Plasma to Limit SARS-CoV-2 Associated Complicat… 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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