Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized With COVID-19
2022; Elsevier BV; Volume: 162; Issue: 5 Linguagem: Inglês
10.1016/j.chest.2022.06.029
ISSN1931-3543
AutoresWesley H. Self, Allison P. Wheeler, Thomas G. Stewart, Harry Schrager, Jason Mallada, Christopher B. Thomas, Vince D. Cataldo, Hollis R. O’Neal, Nathan I. Shapiro, Conor Higgins, Adit A. Ginde, Lakshmi Chauhan, Nicholas J. Johnson, Daniel J. Henning, Stuti J. Jaiswal, Manoj J. Mammen, Estelle S. Harris, Sonal Pannu, Maryrose Laguio‐Vila, Wissam El Atrouni, Marjolein de Wit, Daanish Hoda, Claudia S. Cohn, Carla McWilliams, Carl Shanholtz, Alan E. Jones, Jay S. Raval, Simon Mucha, Tina S. Ipe, Xian Qiao, Stephen Schrantz, Aarthi Shenoy, Richard D. Fremont, Eric Brady, Robert H. Carnahan, James D. Chappell, James E. Crowe, Mark R. Denison, Pavlo Gilchuk, Laura J. Stevens, Rachel E. Sutton, Isaac Thomsen, Sandra Yoder, Amanda J. Bistran-Hall, Jonathan D. Casey, Christopher J. Lindsell, Li Wang, Jill M. Pulley, Jillian P. Rhoads, Gordon R. Bernard, Todd W. Rice,
Tópico(s)COVID-19 Impact on Reproduction
ResumoBackgroundConvalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy.Research QuestionIs rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19?Study Design and MethodsThis was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for < 14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n = 487) or placebo (n = 473). The primary outcome was clinical status (disease severity) 14 days following study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) < 1.0 indicating more favorable outcomes with convalescent plasma than with placebo. In secondary analyses, trial participants were stratified according to the presence of endogenous anti-SARS-CoV-2 antibodies (“serostatus”) at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality.ResultsAmong 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR, 1.04; one-seventh support interval [1/7 SI], 0.82-1.33), in patients without endogenous antibodies (aOR, 1.15; 1/7 SI, 0.74-1.80), or in patients with endogenous antibodies (aOR, 0.96; 1/7 SI, 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89 of 482 (18.5%) patients in the convalescent plasma group and 80 of 465 (17.2%) patients in the placebo group had died (aOR, 1.04; 1/7 SI, 0.69-1.58).InterpretationAmong adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes.Clinical Trial RegistrationClinicalTrials.gov; No.: NCT04362176; URL: www.clinicaltrials.gov Convalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy. Is rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19? This was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for < 14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n = 487) or placebo (n = 473). The primary outcome was clinical status (disease severity) 14 days following study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) < 1.0 indicating more favorable outcomes with convalescent plasma than with placebo. In secondary analyses, trial participants were stratified according to the presence of endogenous anti-SARS-CoV-2 antibodies (“serostatus”) at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality. Among 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR, 1.04; one-seventh support interval [1/7 SI], 0.82-1.33), in patients without endogenous antibodies (aOR, 1.15; 1/7 SI, 0.74-1.80), or in patients with endogenous antibodies (aOR, 0.96; 1/7 SI, 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89 of 482 (18.5%) patients in the convalescent plasma group and 80 of 465 (17.2%) patients in the placebo group had died (aOR, 1.04; 1/7 SI, 0.69-1.58). Among adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes. ClinicalTrials.gov; No.: NCT04362176; URL: www.clinicaltrials.gov Take-home PointsStudy Questions: Is COVID-19 convalescent plasma an efficacious therapy for improving clinical outcomes among adults hospitalized with respiratory symptoms from COVID-19 when administered within 14 days of symptom onset?Results: In this multicenter, blinded, placebo (lactated Ringer’s)-controlled randomized trial among 960 adults hospitalized with COVID-19, patients treated with one unit of convalescent plasma shortly after hospital admission had nearly identical clinical outcomes compared with those treated with placebo, including illness severity on the World Health Organization COVID-19 Clinical Progression Scale 14 days after treatment (aOR, 1.04; 1/7 SI, 0.82-1.33) and 28-day mortality (aOR, 1.04; 1/7 SI, 0.69-1.58).Interpretation: Among adults hospitalized with COVID-19, treatment with neutralizing COVID-19 convalescent plasma did not improve clinical outcomes. Study Questions: Is COVID-19 convalescent plasma an efficacious therapy for improving clinical outcomes among adults hospitalized with respiratory symptoms from COVID-19 when administered within 14 days of symptom onset? Results: In this multicenter, blinded, placebo (lactated Ringer’s)-controlled randomized trial among 960 adults hospitalized with COVID-19, patients treated with one unit of convalescent plasma shortly after hospital admission had nearly identical clinical outcomes compared with those treated with placebo, including illness severity on the World Health Organization COVID-19 Clinical Progression Scale 14 days after treatment (aOR, 1.04; 1/7 SI, 0.82-1.33) and 28-day mortality (aOR, 1.04; 1/7 SI, 0.69-1.58). Interpretation: Among adults hospitalized with COVID-19, treatment with neutralizing COVID-19 convalescent plasma did not improve clinical outcomes. SARS-CoV-2 caused approximately 450 million cases of COVID-19 and 6 million deaths worldwide during the first 2 years of the COVID-19 pandemic.1Johns Hopkins UniversityCOVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University. 2021.https://coronavirus.jhu.edu/map.htmlDate accessed: January 5, 2022Google Scholar,2World Health OrganizationWHO Coronavirus Disease (COVID-19) Dashboard. 2021.https://covid19.who.int/Date accessed: October 20, 2021Google Scholar Since the beginning of the pandemic, passive immunity, including the use of convalescent plasma, has been advanced as a potentially promising approach for treating COVID-19.3Roback J.D. Guarner J. Convalescent plasma to treat COVID-19: possibilities and challenges.JAMA. 2020; 323: 1561-1562Crossref PubMed Scopus (223) Google Scholar, 4Casadevall A. Pirofski L.-A. The convalescent sera option for containing COVID-19.J Clin Invest. 2020; 130: 1545-1548Crossref PubMed Scopus (634) Google Scholar, 5Abraham J. Passive antibody therapy in COVID-19.Nat Rev Immunol. 2020; 20: 401-403Crossref PubMed Scopus (82) Google Scholar, 6Joyner M.J. Carter R.E. Senefeld J.W. et al.Convalescent plasma antibody levels and the risk of death from Covid-19.N Engl J Med. 2021; 384: 1015-1027Crossref PubMed Scopus (345) Google Scholar The rationale for using COVID-19 convalescent plasma relies on the concept of transferring anti-SARS-CoV-2 antibodies from a person who recently recovered from COVID-19 to another person who is in the early stages of infection and has not fully developed his or her own immune response.7Centers for Disease Control and Prevention and Infectious Diseases Society of AmericaCOVID-19 Real-Time Learning Network: Convalescent Plasma. 2021.https://www.idsociety.org/covid-19-real-time-learning-network/therapeutics-and-interventions/convalescent-plasma/Date accessed: July 3, 2021Google Scholar Based on strong biological rationale, COVID-19 convalescent plasma has been widely used during the pandemic.6Joyner M.J. Carter R.E. Senefeld J.W. et al.Convalescent plasma antibody levels and the risk of death from Covid-19.N Engl J Med. 2021; 384: 1015-1027Crossref PubMed Scopus (345) Google Scholar However, most published clinical trial data suggest that COVID-19 convalescent plasma is not efficacious for the most severely ill, hospitalized patients.8Agarwal A. Mukherjee A. Kumar G. et al.Convalescent plasma in the management of moderate Covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial).BMJ. 2020; 371: m3939Crossref PubMed Scopus (462) Google Scholar, 9Simonovich V.A. Burgos Pratx L.D. Scibona P. et al.A randomized trial of convalescent plasma in Covid-19 severe pneumonia.N Engl J Med. 2021; 384: 619-629Crossref PubMed Scopus (589) Google Scholar, 10RECOVERY Collaborative GroupConvalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial.Lancet. 2021; 397: 2049-2059Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar, 11Janiaud P. Axfors C. Schmitt A.M. et al.Association of convalescent plasma treatment with clinical outcomes in patients with COVID-19: a systematic review and meta-analysis.JAMA. 2021; 325: 1185-1195Crossref PubMed Scopus (167) Google Scholar, 12Korley F.K. Durkalski-Mauldin V. Yeatts S.D. et al.Early convalescent plasma for high-risk outpatients with Covid-19.N Engl J Med. 2021; 385: 1951-1960Crossref PubMed Scopus (130) Google Scholar, 13Bégin P. Callum J. Jamula E. et al.Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial.Nat Med. 2021; 27: 2012-2024Crossref PubMed Scopus (148) Google Scholar, 14Estcourt L.J. Turgeon A.F. et al.Writing Committee for the REMAP-CAP InvestigatorsEffect of convalescent plasma on organ support-free days in critically ill patients with COVID-19: a randomized clinical trial.JAMA. 2021; 326: 1690-1702Crossref PubMed Scopus (116) Google Scholar The reasons why prior trials failed to show benefit for convalescent plasma among hospitalized patients with COVID-19 are not conclusively known. If COVID-19 convalescent plasma is beneficial for some patients hospitalized with COVID-19, two potential explanations that may have contributed to null findings in prior trials include: (1) wide variability in the quality (neutralizing activity) of the convalescent plasma used; and (2) inclusion of patients who had already established their own immune response to SARS-CoV-2. Only convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies would be expected to potentially have efficacy. Most prior COVID-19 convalescent plasma trials used antibody-binding assays to select plasma with anti-SARS-CoV-2 antibodies.8Agarwal A. Mukherjee A. Kumar G. et al.Convalescent plasma in the management of moderate Covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial).BMJ. 2020; 371: m3939Crossref PubMed Scopus (462) Google Scholar, 9Simonovich V.A. Burgos Pratx L.D. Scibona P. et al.A randomized trial of convalescent plasma in Covid-19 severe pneumonia.N Engl J Med. 2021; 384: 619-629Crossref PubMed Scopus (589) Google Scholar, 10RECOVERY Collaborative GroupConvalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial.Lancet. 2021; 397: 2049-2059Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar,14Estcourt L.J. Turgeon A.F. et al.Writing Committee for the REMAP-CAP InvestigatorsEffect of convalescent plasma on organ support-free days in critically ill patients with COVID-19: a randomized clinical trial.JAMA. 2021; 326: 1690-1702Crossref PubMed Scopus (116) Google Scholar However the presence of antibodies does not guarantee neutralizing activity,15Gilchuk P. Thomsen I. Yoder S. et al.Standardized two-step testing of antibody activity in COVID-19 convalescent plasma.iScience. 2022; 25103602Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar and most trials did not confirm neutralizing activity of the transfused convalescent plasma.8Agarwal A. Mukherjee A. Kumar G. et al.Convalescent plasma in the management of moderate Covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial).BMJ. 2020; 371: m3939Crossref PubMed Scopus (462) Google Scholar, 9Simonovich V.A. Burgos Pratx L.D. Scibona P. et al.A randomized trial of convalescent plasma in Covid-19 severe pneumonia.N Engl J Med. 2021; 384: 619-629Crossref PubMed Scopus (589) Google Scholar, 10RECOVERY Collaborative GroupConvalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial.Lancet. 2021; 397: 2049-2059Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar,14Estcourt L.J. Turgeon A.F. et al.Writing Committee for the REMAP-CAP InvestigatorsEffect of convalescent plasma on organ support-free days in critically ill patients with COVID-19: a randomized clinical trial.JAMA. 2021; 326: 1690-1702Crossref PubMed Scopus (116) Google Scholar Furthermore, although passive immunity therapies are most likely to be efficacious among patients without an endogenous anti-SARS-CoV-2 immune response, many patients hospitalized with COVID-19 have an endogenous anti-SARS-CoV-2 response by the time of hospital admission,16ACTIV-3/Therapeutics for Inpatients with COVID-19 (TICO) Study GroupEfficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial.Lancet Infect Dis. 2021; 22: 622-635PubMed Google Scholar,17Lundgren J.D. Grund B. et al.ACTIV-3/TICO Bamlanivimab Study GroupResponses to a neutralizing monoclonal antibody for hospitalized patients with COVID-19 according to baseline antibody and antigen levels: a randomized controlled trial.Ann Intern Med. 2022; 175: 234-243Crossref PubMed Scopus (40) Google Scholar and many COVID-19 convalescent plasma trials did not evaluate for efficacy in a population restricted to those without endogenous antibodies.8Agarwal A. Mukherjee A. Kumar G. et al.Convalescent plasma in the management of moderate Covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial).BMJ. 2020; 371: m3939Crossref PubMed Scopus (462) Google Scholar,9Simonovich V.A. Burgos Pratx L.D. Scibona P. et al.A randomized trial of convalescent plasma in Covid-19 severe pneumonia.N Engl J Med. 2021; 384: 619-629Crossref PubMed Scopus (589) Google Scholar Therefore, this trial, Passive Immunity Trial for Our Nation (PassITON), was conducted to test the hypothesis that COVID-19 convalescent plasma with laboratory-confirmed anti-SARS-CoV-2 neutralizing activity improves clinical outcomes when administered to adults hospitalized with COVID-19 and to provide separate efficacy estimates for patients who did and did not have endogenous anti-SARS-CoV-2 antibodies prior to treatment. The rationale and design of this trial have been previously published18Self W.H. Stewart T.G. Wheeler A.P. et al.Passive Immunity Trial for Our Nation (PassITON): study protocol for a randomized placebo-control clinical trial evaluating COVID-19 convalescent plasma in hospitalized adults.Trials. 2021; 22: 221Crossref PubMed Scopus (11) Google Scholar and are available in the protocol and statistical analysis plan included as Supplemental Data. We conducted a multicenter, blinded, placebo-controlled, randomized clinical trial to study the efficacy and safety of COVID-19 convalescent plasma as a treatment for adults hospitalized with COVID-19. Patients were enrolled at 25 US hospitals (e-Table 1) between April 28, 2020, and June 1, 2021. The trial started as a single center study at Vanderbilt University Medical Center with funding from the Dolly Parton COVID-19 Research Fund and then expanded to a multicenter study in September 2020 with funding from the National Center for Advancing Translational Sciences (NCATS). A central institutional review board at Vanderbilt University Medical Center approved the study. An independent Data and Safety Monitoring Board provided trial oversight. COVID-19 convalescent plasma was used in the trial under US Food and Drug Administration Investigational New Drug number 21080. Participants or legally authorized representatives provided written informed consent prior to trial participation. We enrolled adults hospitalized with laboratory-confirmed SARS-CoV-2 infection and respiratory symptoms consistent with COVID-19 for < 14 days. These individuals included patients hospitalized on general medical floors and in ICUs, including those receiving no oxygen therapy, standard oxygen therapy, high-flow oxygen therapy, noninvasive ventilation, or invasive mechanical ventilation. Major exclusion criteria were prior COVID-19 vaccination, use of a COVID-19 passive immunity therapy in the prior 30 days, and contraindication to blood product transfusion. Full eligibility criteria are listed in e-Methods Section A. Using a centralized, web-based Research Electronic Data Capture platform,19Harris P.A. Taylor R. Minor B.L. et al.The REDCap consortium: building an international community of software platform partners.J Biomed Informatics. 2019; 95103208Crossref PubMed Scopus (7624) Google Scholar enrolled patients were randomized in a 1:1 ratio to receive COVID-19 convalescent plasma or placebo stratified according to site, sex, and age. The placebo solution was lactated Ringer’s with multivitamin additives, which matched the color of plasma, and the study product was covered with masking bags during infusion. To safely administer blood products and maintain blinding of study group assignment, the trial used both blinded and unblinded study personnel at each site. Patients, investigators, outcome assessors, and treating providers remained blinded. Unblinded personnel included the study team member who randomized the patient and personnel in the blood bank and investigational pharmacy (e-Methods Section B). Most of the convalescent plasma used in this trial was collected by trial-specific plasma donation drives at Vanderbilt University Medical Center in collaboration with Blood Assurance between April 22, 2020, and April 3, 2021. During the single-center component of the trial (prior to October 1, 2020), convalescent plasma units were selected based on serum concentration of IgG against the SARS-CoV-2 receptor binding domain (RBD) being ≥ 256 World Health Organization (WHO) EU/mL. With initiation of the multicenter component of the trial, neutralization testing was added to the plasma selection process such that selected plasma units showed neutralizing function, defined as a half-maximal neutralization titer ≥ 50 (NT50 ≥ 50) using a replication-competent chimeric vesicular stomatitis virus expressing the SARS-CoV-2 spike protein (e-Methods Section C).15Gilchuk P. Thomsen I. Yoder S. et al.Standardized two-step testing of antibody activity in COVID-19 convalescent plasma.iScience. 2022; 25103602Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar,18Self W.H. Stewart T.G. Wheeler A.P. et al.Passive Immunity Trial for Our Nation (PassITON): study protocol for a randomized placebo-control clinical trial evaluating COVID-19 convalescent plasma in hospitalized adults.Trials. 2021; 22: 221Crossref PubMed Scopus (11) Google Scholar In the spring of 2021, a total of 11 units of COVID-19 convalescent plasma units were supplied by Vitalant, a commercial US-based blood bank. Patients randomized to the convalescent plasma group received an IV infusion of a single unit (200-399 mL) of ABO-compatible COVID-19 convalescent plasma. Patients randomized to receive placebo received a single 250 mL IV infusion of lactated Ringer’s solution with multivitamin additives. The study infusion was delivered as soon as possible and within 24 h of randomization. Use of open-label convalescent plasma in the 14 days following the study infusion was a protocol deviation. Enrollment in other COVID-19 clinical trials, such as those evaluating anti-SARS-CoV-2 monoclonal antibody therapies, was not permitted. Other aspects of clinical management, including the use of remdesivir, corticosteroids, immunomodulators, and oxygen therapy, were performed by the treating clinicians without influence from the study protocol. Concomitant medications were recorded through hospital discharge. Plasma donors had serum specimens collected at the time of their donation. These specimens were tested for IgG antibodies against the SARS-CoV-2 RBD and for neutralization of a virus displaying the SARS-CoV-2 spike protein.15Gilchuk P. Thomsen I. Yoder S. et al.Standardized two-step testing of antibody activity in COVID-19 convalescent plasma.iScience. 2022; 25103602Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Using these results, convalescent plasma units were characterized in terms of anti-RBD antibody quantification and neutralization titers (e-Methods Section D). Trial participants had serum specimens collected at baseline (following consent for trial participation and prior to study product infusion) and postinfusion (approximately 24 h after study product infusion). These samples were tested with the same quantitative anti-RBD antibody assay. Patients with a baseline serum specimen with ≤ 3.0 WHO EU/mL on the anti-RBD assay were classified as “seronegative,” indicating no endogenous anti-SARS-CoV-2 antibodies detected prior to the study infusion (e-Methods Section D). The primary outcome was the patient’s clinical status (disease severity) 14 days following the study infusion on a seven-category ordinal scale (the COVID-19 Clinical Progression Scale). The seven categories were: (1) not hospitalized with resumption of normal pre-illness activities; (2) not hospitalized but unable to resume normal pre-illness activities (including use of home supplemental oxygen by patients who did not use home oxygen pre-illness); (3) hospitalized and not on supplemental oxygen; (4) hospitalized and on standard-flow supplemental oxygen; (5) hospitalized and on high-flow oxygen therapy or noninvasive mechanical ventilation; (6) hospitalized and on invasive mechanical ventilation or extracorporeal membrane oxygenation; and (7) death. While the patient was hospitalized, the ordinal scale category was identified by direct patient observation and medical record review. Following hospital discharge, patients were contacted by telephone to distinguish between category 1 and 2 using questions consistent with validated health status measures.20EuroQol GroupEuroQol—a new facility for the measurement of health-related quality of life.Health Policy. 1990; 16: 199-208Crossref PubMed Scopus (11902) Google Scholar,21Herdman M. Gudex C. Lloyd A. et al.Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L).Qual Life Res. 2011; 20: 1727-1736Crossref PubMed Scopus (4804) Google Scholar This scale was developed by the WHO as a patient-centered outcome for COVID-19 trials22World Health Organization (WHO). WHO R&D Blueprint-Novel Coronavirus, COVID-19 Therapeutic Trial Synopsis. 2020. Accessed July 5, 2021. WHO R&D Blueprint-Novel Coronavirus, COVID-19 Therapeutic Trial Synopsis. https://www.who.int/teams/blueprint/covid-19Google Scholar and has been used in multiple prior trials.23Self W.H. Semler M.W. Leither L.M. et al.Effect of hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: a randomized clinical trial.JAMA. 2020; 324: 2165-2176Crossref PubMed Scopus (265) Google Scholar, 24Lundgren J.D. Grund B. et al.ACTIV-3/TICO LY-CoV555 Study GroupA neutralizing monoclonal antibody for hospitalized patients with Covid-19.N Engl J Med. 2021; 384: 905-914Crossref PubMed Scopus (269) Google Scholar, 25Beigel J.H. Tomashek K.M. Dodd L.E. et al.Remdesivir for the treatment of Covid-19—final report.N Engl J Med. 2020; 383: 1813-1826Crossref PubMed Scopus (4549) Google Scholar, 26Spinner C.D. Gottlieb R.L. Criner G.J. et al.Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial.JAMA. 2020; 324: 1048-1057Crossref PubMed Scopus (836) Google Scholar The trial included 13 secondary efficacy outcomes, including: all-cause, all-location mortality at 14 and 28 days; clinical status on the COVID-19 Clinical Progression Scale at 2, 7, and 28 days; time to hospital discharge; time to recovery (defined as the earlier of oxygen liberation or hospital discharge); and several types of support-free days through day 28, including hospital-free days, oxygen-free days, ICU-free days, ventilator-free days, and vasopressor-free days. The key safety outcome was clinical evidence of a transfusion reaction within 6 h of initiation of the study infusion. Details of each outcome are described in e-Methods Section E. The trial was designed and analyzed with a likelihood framework27Wald A. Sequential tests of statistical hypotheses.Ann Math Statist. 1945; 16: 117-186Crossref Google Scholar,28Wang S.-J. Blume J.D. An evidential approach to non-inferiority clinical trials.Pharmaceut Statist. 2011; 10: 440-447Crossref PubMed Scopus (12) Google Scholar because rapid changes in the COVID-19 pandemic could result in a need to change the interim analysis schedule or sample size. An analysis plan using the likelihood approach retains interpretability when such changes are made.29Royall R. Statistical Evidence: A Likelihood Paradigm. Chapman and Hall, London, England1997Google Scholar,30Blume J.D. Likelihood methods for measuring statistical evidence.Statist Med. 2002; 21: 2563-2599Crossref PubMed Scopus (106) Google Scholar Efficacy outcomes were analyzed in the intention-to-treat population, which comprised all randomized patients who did not withdraw consent, by comparing patients randomized to the convalescent plasma group vs the placebo group, with the placebo group serving as the referent. The primary outcome was analyzed with a multivariable cumulative probability ordinal regression model with logit link adjusted for the following baseline (preinfusion) characteristics: age, sex, Sequential Organ Failure Assessment score, COVID-19 Clinical Progression Scale category, duration of COVID-19 symptoms, and enrolling site (as a random effect). Model output was an adjusted OR (aOR), with an aOR < 1.0 indicating more favorable outcomes on the scale in the convalescent plasma group compared with the placebo group. Uncertainty for the aOR was quantified with a one-seventh support interval (1/7 SI), which can be interpreted similarly to 95% CIs; however, unlike 95% CIs, SIs maintain interpretability if circumstances require changes to the timing or frequency of interim analyses. The prespecified target sample size was 1,000 participants. Power of the trial with 1,000 participants was estimated via simulations as described in the Statistical Analysis Plan. These simulations showed that while maintaining a type I error rate < 0.05, a sample size of 1,000 patients would provide 80% power to detect an aOR for the primary outcome ≤ 0.73, a difference considered clinically important in prior COVID-19 trials.23Self W.H. Semler M.W. Leither L.M. et al.Effect of hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: a randomized clinical trial.JAMA. 2020; 324: 2165-2176Crossref PubMed Scopus (265) Google Scholar,25Beigel J.H. Tomashek K.M. Dodd L.E. et al.Remdesivir for the treatment of Covid-19—final report.N Engl J Med. 2020; 383: 1813-1826Crossref PubMed Scopus (4549) Google Scholar,26Spinner C.D. Gottlieb R.L. Criner G.J. et al.Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial.JAMA. 2020; 324: 1048-1057Crossref PubMed Scopus (836) Google Scholar The trial had three planned interim analyses after primary outcome data were available for approximately 150, 450, and 750 patients, and had flexibility to add interim analyses based on changes in the pandemic or emerging data on COVID-19 convalescent plasma. In a secondary analysis, the primary outcome was analyzed in an as-treated population, consisting of patients in the intention-to-treat population who started the assigned study infusion (ie, who received any volume of the assigned convalescent plasma vs placebo solution). Heterogeneity of treatment effect for the primary outcome by baseline characteristics was assessed for the following variables: trial participant’s serum anti-RBD antibody concentration; duration of COVID-19 symptoms; age; race/ethnicity; indicators of illness severity; plasma donor’s serum anti-RBD antibody concentration; and plasma donor’s anti-SARS-CoV-2 neutralization titer. Secondary efficacy outcomes were analyzed in the intention-to-treat population using multivariable regression models with the same covariates as the model for the primary outcome (e-Methods Section E). Safety outcomes and adverse events were analyzed without covariate adjustment. The presentation of results included between-group differences with 1/7 SIs. Results with a 1/7 SI that did not cross the null were deemed to reflect a statistical difference. The widths of SIs were not adjusted for multiplicity. Analyses were conducted with R version 4.1.1 (R Foundation for Statistical Computing) and STATA 16.1 (StataCorp). On June 1, 2021, a fourth interim analysis was completed, at which time 974 (97.4%) p
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