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What is the effect of convalescent plasma therapy added to standard treatment, compared with standard treatment alone, on clinical outcomes in patients with severe or life-threatening coronavirus disease 2019 (COVID-19)?
In this randomized clinical trial that included 103 patients and was terminated early, the hazard ratio for time to clinical improvement within 28 days in the convalescent plasma group vs the standard treatment group was 1.40 and was not statistically significant.
Among patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment did not significantly improve the time to clinical improvement within 28 days, although the trial was terminated early and may have been underpowered to detect a clinically important difference.
Convalescent plasma is a potential therapeutic option for patients with coronavirus disease 2019 (COVID-19), but further data from randomized clinical trials are needed.
To evaluate the efficacy and adverse effects of convalescent plasma therapy for patients with COVID-19.
Design, Setting, and Participants
Open-label, multicenter, randomized clinical trial performed in 7 medical centers in Wuhan, China, from February 14, 2020, to April 1, 2020, with final follow-up April 28, 2020. The trial included 103 participants with laboratory-confirmed COVID-19 that was severe (respiratory distress and/or hypoxemia) or life-threatening (shock, organ failure, or requiring mechanical ventilation). The trial was terminated early after 103 of a planned 200 patients were enrolled.
Convalescent plasma in addition to standard treatment (n = 52) vs standard treatment alone (control) (n = 51), stratified by disease severity.
Main Outcomes and Measures
Primary outcome was time to clinical improvement within 28 days, defined as patient discharged alive or reduction of 2 points on a 6-point disease severity scale (ranging from 1 [discharge] to 6 [death]). Secondary outcomes included 28-day mortality, time to discharge, and the rate of viral polymerase chain reaction (PCR) results turned from positive at baseline to negative at up to 72 hours.
Of 103 patients who were randomized (median age, 70 years; 60 [58.3%] male), 101 (98.1%) completed the trial. Clinical improvement occurred within 28 days in 51.9% (27/52) of the convalescent plasma group vs 43.1% (22/51) in the control group (difference, 8.8% [95% CI, −10.4% to 28.0%]; hazard ratio [HR], 1.40 [95% CI, 0.79-2.49]; P = .26). Among those with severe disease, the primary outcome occurred in 91.3% (21/23) of the convalescent plasma group vs 68.2% (15/22) of the control group (HR, 2.15 [95% CI, 1.07-4.32]; P = .03); among those with life-threatening disease the primary outcome occurred in 20.7% (6/29) of the convalescent plasma group vs 24.1% (7/29) of the control group (HR, 0.88 [95% CI, 0.30-2.63]; P = .83) (P for interaction = .17). There was no significant difference in 28-day mortality (15.7% vs 24.0%; OR, 0.59 [95% CI, 0.22-1.59]; P = .30) or time from randomization to discharge (51.0% vs 36.0% discharged by day 28; HR, 1.61 [95% CI, 0.88-2.95]; P = .12). Convalescent plasma treatment was associated with a negative conversion rate of viral PCR at 72 hours in 87.2% of the convalescent plasma group vs 37.5% of the control group (OR, 11.39 [95% CI, 3.91-33.18]; P < .001). Two patients in the convalescent plasma group experienced adverse events within hours after transfusion that improved with supportive care.
Conclusion and Relevance
Among patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment, compared with standard treatment alone, did not result in a statistically significant improvement in time to clinical improvement within 28 days. Interpretation is limited by early termination of the trial, which may have been underpowered to detect a clinically important difference.
Chinese Clinical Trial Registry: ChiCTR2000029757
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Corresponding Authors: Zhong Liu, MD, PhD, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, 26 Huacai Rd, Longtan Industry Zone, Chenghua District, 610052, Chengdu, Sichuan, China (email@example.com); Yanyun Wu, MD, PhD, University of Miami, Department of Pathology, 1611 NW 12th Ave, Miami, FL 33136 (firstname.lastname@example.org).
Accepted for Publication: May 23, 2020.
Published Online: June 3, 2020. doi:10.1001/jama.2020.10044
Correction: This article was corrected on August 4. 2020, to fix some odds ratios in the Abstract, Results, and Table 3; some baseline laboratory data in Table 1; corresponding data in Supplement 3; and eFigure 1.
Author Contributions: Dr Z. Liu had full access to all of the data in this study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs L. Li, W. Zhang, and Y. Hu are co–first authors. Drs L. Li, W. Zhang, Y. Hu, X. Tong, S. Zheng, J. Yang, Y. Kong, L. Ren, Q. Wei, H. Mei, C. Hu, C. Tao, R. Yang, J. Wang, and Y. Yu contributed equally to the study.
Concept and design: L. Li, W. Zhang, X. Tong, J. Yang, N. Xiong, L. Zhang, J.W. Wang, Y. Wu, Z. Liu.
Acquisition, analysis, or interpretation of data: W. Zhang, S. Zheng, Y. Kong, L. Ren, Q. Wei, H. Mei, C. Hu, C. Tao, R. Yang, Jue Wang, Y. Yu, Y. Guo, X. Wu, Z. Xu, N. Xiong, L. Chen, Juan Wang, N. Man, Y. Liu, H. Xu, E. Deng, X. Zhang, C. Li, C. Wang, S. Su, Y. Hu, Y. Wu, Z. Liu.
Drafting of the manuscript: L. Li, W. Zhang, Y. Kong, L. Ren, H. Xu, E. Deng, C. Wang, Y. Wu, Z. Liu.
Critical revision of the manuscript for important intellectual content: W. Zhang, X. Tong, S. Zheng, J. Yang, Q. Wei, H. Mei, C. Hu, C. Tao, R. Yang, Jue Wang, Y. Yu, Y. Guo, X. Wu, Z. Xu, L. Zeng, N. Xiong, L. Chen, Juan Wang, N. Man, Y. Liu, X. Zhang, C. Li, S. Su, L. Zhang, Juan Wang, Y. Hu, Y. Wu, Z. Liu.
Statistical analysis: J. Yang, Y. Kong, Y. Yu.
Obtained funding: L. Li, Z. Liu.
Administrative, technical, or material support: L. Li, W. Zhang, X. Tong, L. Ren, H. Mei, Jue Wang, Y. Guo, N. Xiong, Y. Liu, H. Xu, E. Deng, C. Wang, S. Su, J.W. Wang, Z. Liu.
Supervision: W. Zhang, J. Yang, H. Mei, Y. Hu.
Conflict of Interest Disclosures: Dr Liu reports holding a pending patent on COVID-19 testing. Dr Wu reports consulting for Verax Medical and Grifols, receiving royalties from UptoDate and AABB, and being a volunteer visiting professor and receiving travel support for giving medical education from the Chinese Institute of Blood Transfusion. No other disclosures were reported.
Funding/Support: This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS) grants 2020-I2M-CoV19-006, 2016-I2M-3-024 (Dr Z. Liu), and 2017-I2M-1-009 (Dr L. Li) and the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences grant 2018PT32016 (Dr Z. Liu).
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 4.
Additional Contributions: We would like to thank the following individuals for their guidance, expertise, and assistance with the study design: Peter W. Marks, MD, PhD, Center for Biologics Evaluation and Research, FDA; Anne Eder, MD, PhD, Center for Biologics Evaluation and Research, FDA; Nicole Verdun, MD, Center for Biologics Evaluation and Research, FDA; Tim Uyeki, MD, MPH, MPP, National Center for Immunization and Respiratory Diseases, CDC; Scott Koepsell, MD, PhD, University of Nebraska Medical Center; Annie Winkler, MD, Instrumentation Laboratory; Xuan Qin, PhD, Seattle Children’s Hospital and University of Washington. None received compensation related to this study.
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