Passive Immunity Trial for Our Nation (PassITON): study protocol for a randomized placebo-control clinical trial evaluating COVID-19 convalescent plasma in hospitalized adults

Background: Convalescent plasma is being used widely as a treatment for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of COVID-19 convalescent plasma is unclear. Methods: The Passive Immunity Trial for Our Nation (PassITON), is a multicenter, placebo-controlled, blinded, randomized clinical trial being conducted in the United States to provide high-quality evidence on the efficacy of COVID-19 convalescent plasma as a treatment for adults hospitalized with symptomatic disease. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days are eligible. Enrolled patients are randomized in a 1:1 ratio to 1 unit (200–399 mL) of COVID-19 convalescent plasma that has demonstrated neutralizing function using a SARS-CoV-2 chimeric virus neutralization assay. Study treatments are administered in a blinded fashion and patients are followed for 28 days. The primary outcome is clinical status 14 days after study treatment as measured on a 7-category ordinal scale assessing mortality, respiratory support, and return to normal activities of daily living. Key secondary outcomes include mortality and oxygen-free days. The trial is projected to enroll 1000 patients and is designed to detect an odds ratio ≤ 0.73 for the primary outcome. Discussion: This trial will provide the most robust data available to date on the efficacy of COVID-19 convalescent plasma for the treatment of adults hospitalized with acute moderate to severe COVID-19. These data will be useful to guide the treatment of COVID-19 patients in the current pandemic and for informing decisions about whether developing a standardized infrastructure for collecting and disseminating convalescent plasma to prepare for future viral pandemics is indicated. Trial Registration: ClinicalTrials.gov: NCT04362176. Date of trial registration: April 24, 2020, https://clinicaltrials.gov/ct2/show/NCT04362176


Background
Since emerging in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global health crisis. (1) The disease caused by SARS-CoV-2 infection, coronavirus disease 19 (COVID- 19), has caused over 2.1 million deaths worldwide through January 2021. (2) Despite vast ongoing efforts to identify potential treatments for patients with acute COVID-19, few therapies have demonstrated bene t, and these drugs appear to only be effective for certain subgroups of patients with COVID-19. (3,4) The recent approval of two vaccines offers promise for preventing new infections in the future. (5,6) However, logistics of manufacturing and deploying the vaccine worldwide appear challenging, especially in resource-poor and developing nations. (7)(8)(9) Additionally, many people appear reluctant to receive SARS-CoV-2 vaccines even when they do become widely available.(10) Furthermore, vaccines are unlikely to completely eliminate COVID-19 in vaccinated populations. (11)(12)(13)(14) Thus, COVID-19 may be a major cause of morbidity and mortality for the foreseeable future and effective therapies to treat patients moderately and severely ill with COVID-19 are urgently needed.
Rationale for convalescent plasma as a therapy for COVID-19 The use of convalescent plasma as a therapy for acute infections relies on the concept of transferring neutralizing antibodies from a person who recently recovered from the disease and developed a robust pathogen-speci c immune response to another person who is in the early stages of the infection and has not fully developed his or her own immune response. This type of therapy is often called passive immune therapy or passive antibody therapy.
Based on strong biological rationale, convalescent plasma has been used for more than a century to treat outbreaks of viral diseases, especially when therapeutic options have been lacking. (15,16) However, convalescent plasma therapy has rarely been evaluated by rigorously designed randomized trials, resulting in little empiric evidence to support its use. Argentine hemorrhagic fever is the only viral illness for which convalescent plasma was conclusively shown to be e cacious. (17) Expanded Access Program and Emergency Use Authorization Despite limited data on e cacy, hundreds of thousands of patients have received COVID-19 convalescent plasma outside of a clinical trial. The expanded access program (EAP) in the US for COVID-19 convalescent plasma was started in April 2020. More than 90,000 patients were treated in through this program, which was primarily designed to provide access to convalescent plasma early in the pandemic and only secondarily to evaluate safety and effectiveness. (18,19) Less than 1% of treated patients experienced a transfusion reaction. (20) Because the program did not include a control group, e cacy was assessed by comparing clinical outcomes among patients who received convalescent plasma with high, medium, and low levels of SARS-CoV-2 antibodies, using the concept that better clinical outcomes in patients who received plasma with higher antibody levels would suggest e cacy. (21) Antibody levels were retrospectively measured with the Ortho-Clinical Diagnostics VITROS IgG semiquantitative assay and classi ed into the following three groups: (1) high antibody level (signal-to-cutoff ratio >18.45); (2) medium antibody level (signal-to-cutoff ratio 4.62 -18.45); and (3) low antibody level (signal-to-cutoff <4.62). Among 3,082 patients who received a single unit of convalescent plasma with measured antibody levels, and thus could be assigned to a single category of antibody level, 30-day mortality varied in a "dose-dependent" pattern by antibody titer level: 22.3% mortality in the high titer group, 27.4% in the medium titer group, and 29.6% in the low titer group. (19) Citing results of the EAP, along with a small trial from China(22) and a trial from the Netherlands(23) that halted early, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) on August 23, 2020 for COVID-19 convalescent plasma to treat hospitalized COVID-19 patients. (20) At that time, the FDA concluded that existing evidence suggested that COVID-19 convalescent plasma with high antibody titer may be bene cial but emphasized that additional high-quality randomized clinical trials were important to more de nitively understand the e cacy of COVID-19 convalescent plasma.
Clinical trials of COVID-19 convalescent plasma COVID-19 convalescent plasma trials published after announcement of the EUA include the PLACID (24) and PlasmAR(25) trials conducted among hospitalized adults in India and Argentina, respectively, and another trial of older outpatient adults in Argentina. (26) Neither PLACID nor PlasmAR suggested e cacy for COVID-19 convalescent plasma. PLACID enrolled 464 patients randomized to convalescent plasma administered in two 200 mL doses versus usual care in an unblinded fashion. Neutralizing capacity of the plasma was measured retrospectively and less than one-third of the units transfused in the study possessed neutralizing antibody titers ≥1:80 by a microneutralization assay. The randomized, blinded, placebo-controlled PlasmAR trial enrolled 335 patients in a 2:1 convalescent plasma-to-placebo ratio. Convalescent plasma units were chosen for transfusion if they were found to have SARS-CoV-2 IgG titers 1:800 by the COVIDAR assay. Retrospective analysis of neutralizing titers in 125 (56%) of the infused doses showed an 80% inhibitory concentration median titer of 1:300. Treatment with convalescent plasma in this trial did not signi cantly improve clinical status at 30 days as measured on a six-level ordinal scale. A subsequent meta-analysis of available observational studies and clinical trials involving hospitalized patients suggested potential e cacy for COVID-19 convalescent plasma. (27) Libster et al. conducted a randomized trial of 160 outpatients who were ≥65 years old with mild COVID-19 and symptoms <72 hours. (26) Participants were randomized in a 1:1 ratio to "high titer" COVID-19 convalescent plasma (IgG titer greater than 1:1000 against the spike protein) or placebo. Progression to severe respiratory disease, de ned as a respiratory rate ≥30 breaths/minute or oxygen saturation <93% while breathing room air, occurred in fewer patients randomized to convalescent plasma (16%) than placebo (31%), suggesting COVID-19 convalescent plasma treatment may be e cacious for early, mild disease. (26) Results from these trials published after the FDA emergency use authorization were unknown at the time that PassITON was designed. However, it is noteworthy that unlike PassITON, many prior studies of COVID-19 convalescent plasma either did not quantify SARS-CoV-2 antibody titers or screened convalescent plasma units for SARS-CoV-2 antibodies with binding assays without testing for neutralization. Among patients with high detectable levels of SARS-CoV-2 antibodies, only approximately 40-50% appear to have neutralizing function.(28) Therefore, many prior COVID-19 convalescent plasma studies likely included plasma units without neutralizing function.

Goal of this trial
Rigorous clinical trials evaluating the e cacy COVID-19 convalescent plasma with neutralizing activity are needed to guide clinical practice regarding the use of convalescent plasma during the current pandemic and also to understand if developing a scalable infrastructure for collecting, testing, and disseminating convalescent plasma is an important investment to prepare for future outbreaks of novel viruses. Convalescent plasma could be an immediately available therapy in the early stages of future viral pandemics in resource-rich and resource-limited nations. Understanding the e cacy of convalescent plasma in the current COVID-19 pandemic could help inform decisions on pursuing convalescent plasma as a therapy for future pandemics.
This study-the Passive Immunity Trial for Our Nation (PassITON)-was designed to provide the highest quality evidence on the e cacy of COVID-19 convalescent plasma as a therapy for adults hospitalized with moderate-to-severe acute COVID-19.

Design and oversight
PassITON is a multicenter, blinded, placebo-controlled, randomized clinical trial evaluating the e cacy of COVID-19 convalescent plasma with neutralizing antibodies for the treatment of adults hospitalized with acute COVID-19. Progress and safety of the trial is monitored by an independent Data and Safety Monitoring Board (DSMB). Prior to initiation of study procedures, informed consent is obtained by a trained study coordinator or investigator from each patient or a legally authorized surrogate decision maker if the patient is unable to make medical decisions. Consent is obtained electronically or on paper. The trial protocol was developed according to the SPIRIT guidelines (Supplementary Materials, Supplemental Figure 1). Protocol modi cations and changes to study-related procedures are communicated to the study team and investigators through twice weekly internal coordinating center team meetings, weekly PassITON newsletters disseminated both internally and externally to site staff and investigators, and biweekly Steering Committee meetings attended by site investigators and coordinators.

Collection of convalescent plasma
The plasma collection component of PassITON was developed to optimize the e cient procurement of COVID-19 convalescent plasma with high levels of neutralizing antibodies. Convalescent plasma is collected from adults mainly residing around Nashville, Tennessee who have recovered from COVID-19 in a collaborative effort between Vanderbilt University Medical Center and Blood Assurance, a nonpro t regional blood center based in Chattanooga, Tennessee. Patients with laboratory-con rmed SARS-CoV-2 infection with self-reported symptom severity of at least 3 on a 10-point scale (range: 1, "I feel healthy" to 10, "I was/should have been in the Intensive Care Unit (ICU)") are eligible for plasma donation. Recovered patients are identi ed through several methods including Vanderbilt hospital records, mass email through the Vanderbilt employee list, public advertising in the community, Research-Match (29,30), and selfidenti cation. Patients are able to donate plasma if they have recovered from acute COVID-19, de ned as either: 1) being symptom free for 14 days and having at least one negative COVID-19 test by RT-PCR, or 2) being symptom free for at least 28 days. All donors must also meet FDA requirements for blood product donation.(31) Donors sign an IRB approved informed consent for participation prior to phlebotomy. Donors have a blood sample collected for characterization of circulating SARS-CoV-2 antibodies (see next section) and then immediately have blood collected for plasma donation units ( Figure 1).
Plasma collection is performed via apheresis using the Fresenius-Kabi ALYX instrument, which allows for the collection of up to four units per donation. Patients are invited to return for additional donations if antibody testing demonstrates high antibody levels (≥20,000 EU/mL by anti-Receptor Binding Domain (RBD) IgG binding assay) and neutralizing activity. Through an FDA variance obtained by Blood Assurance, participants are allowed to donate as frequently as every 7 days for 4 visits before evaluation of total protein and serum albumin to con rm safety of continued donations. Beginning October 1, 2020, an additional screening step was introduced to con rm the presence of SARS-CoV-2 neutralizing antibodies. In the modi ed format, donor samples still undergo screening via the Abbott TM ARCHITECT TM platform and the RBD Luminex assay. Samples are excluded if they are found to be negative via the Abbott TM ARCHITECT TM of have an MFI < 8000 as determined by the RBD Luminex assay. Samples with an antibody level (MFI) above 8000 are then screened for the ability to neutralize virus by functional assessment with a high-throughput assay platform using real-time, quantitative cellular analysis on the xCELLigence platform (Agilent Technologies, Santa Clara, CA), using chimeric vesicular stomatitis virus (VSV) expressing intact SARS-CoV-2 spike protein, as previously described.

Trial participants
Patients eligible for enrollment in the trial include adults hospitalized with laboratory-con rmed SARS-CoV-2 infection and respiratory symptoms consistent with COVID-19 for fewer than 14 days. Patients hospitalized in either ICU or less intensive areas are eligible. Major exclusion criteria include planned hospital discharge within 24 hours and prior receipt of COVID-19 convalescent plasma or another passive immunity therapy in the prior 30 days.

Randomization and treatment groups
Enrolled patients are randomized in a 1:1 ratio to COVID-19 convalescent plasma or placebo. Randomization is completed by a centralized web-based platform and strati ed by site, sex, and age. Patients randomized to convalescent plasma receive a single dose of 1 unit (200-399 mL) of COVID-19 convalescent plasma infused intravenously. Patients randomized to placebo receive a single 250 mL dose of lactated Ringer's solution containing multivitamin infused intravenously. Multivitamins are added to the placebo solution to produce a yellow color that matches the color of plasma.
The study infusion (convalescent plasma or placebo) is administered as soon as possible and within 24 hours after randomization. Infusion of study treatment is halted if the study participant exhibits any symptoms of transfusion reaction or anaphylaxis. Patients are observed for 6 hours after initiation of the study infusion for signs and symptoms of a transfusion reaction. Use of open-label convalescent plasma is strongly discouraged for the rst 14 days following the study infusion. Other aspects of clinical management are performed at the discretion of the treating clinicians without in uence from the study protocol.

Blinding
In order to safely administer a blood product in the trial and also maintain blinding of the patient, investigators, and outcome assessors, the trial uses both blinded and unblinded study personnel. At each site, the lead investigator remains blinded to study group assignment. An unblinded study member randomizes patients, receives the treatment assignment, and then orders convalescent plasma or the placebo solution based on the randomized treatment assignment. The study treatment is delivered to the patient's bedside, where an unblinded clinical nurse places the study treatment in a blinding bag before entering the patient's room. The unblinded clinical nurse then infuses the treatment. Clinical monitoring, including vital sign assessment, is completed based on local practices for monitoring an infusion of plasma regardless of randomized group. The clinical providers (e.g. physicians), patient, and outcome assessors remain blinded to study group assignment. Participant unblinding is performed by unblinded site coordinators and is permitted only after the study follow-up period is complete and if unblinding will directly impact the individual's course of clinical care (e.g. timing of COVID-19 vaccination).

Outcomes
The primary outcome is the patient's clinical status on a 7-category ordinal scale (the COVID-19 7point Ordinal Clinical Progression Outcomes Scale) 14 days after the study infusion. The 7 categories are: 1. not hospitalized with resumption of normal activities; 2. not hospitalized, but unable to resume normal activities; 3. hospitalized, not on supplemental oxygen; 4. hospitalized, and on supplemental oxygen; 5. hospitalized, on nasal high-ow oxygen therapy, noninvasive mechanical ventilation, or both; 6. hospitalized, on ECMO, invasive mechanical ventilation, or both.; and 7. death. While the patient is hospitalized, the ordinal scale category is identi ed by direct patient observation and medical record review. After hospital discharge, patients are contacted by telephone to distinguish between category 1 and category 2. This scale was developed by the World Health Organization (35) (WHO) early in the pandemic as a patient-centered clinical outcome for COVID-19 and has been successfully used in multiple clinical trials. (3,36,37) Secondary and safety outcomes are shown in Table 1.

Data Collection, Monitoring, and Dissemination
Randomization and data collection are be conducted through Research Electronic Data Capture (REDCap). The randomization module in REDCap allows the statistician to load a randomization table that will allow the study personnel to click a 'randomize' button. REDCap is a secure, web-based application designed to support data capture for research studies, providing 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for importing data from external sources.
Data quality is reviewed remotely using front-end range and logic checks at the time of data entry and back-end monitoring of data using application programming interface tools connecting the online database to statistical software to generate data reports. Patient records and case report forms are also be reviewed to evaluate the accuracy and completeness of the data entered into the database and monitored for protocol compliance per the study monitoring plan.
The data generated from the PassItOn trial will released via publication. It will also be shared at seminars, symposiums, and meeting presentations as well as deposited in appropriate databases. Before releasing any of this information, the raw data will be stripped of identi ers in order to remain compliant with HIPAA and other governing agencies' guidelines.

Statistical analysis
In this section, we describe key statistical features of the trial. The full statistical analysis plan for the trial is included in the Supplemental Materials.

General approach to analysis
The statistical design for this trial was informed by the need to learn as rapidly as possible from the data during the pandemic while simultaneously managing the risk of drawing erroneous conclusions. Rapid decision making to maximally inform clinical care during an ongoing pandemic requires exibility for the DSMB to perform unplanned evaluations of the data and potentially decrease or increase the sample size of the trial. This requires a trial framework that does not demand that all possible interim analyses are prespeci ed, as is required of approaches using p-values. Two closely related approaches which offer the needed exibility are the Likelihood and Bayesian frameworks. We selected the Likelihood framework for this trial. The Likelihood approach has been successfully implemented in clinical trials with continuous monitoring or sequential methods (38,39), because it retains its meaning and reliability regardless of the number of interim analyses or outcomes under consideration. (40,41) Decision making using the likelihood approach in a clinical trial centers on three quantities: the point estimate of the treatment effect (an odds ratio, for example), a corresponding interval estimate, and a single number summary that measures the relative evidence for one hypothesis (for example, convalescent plasma being superior to placebo) compared to another hypothesis (for example, convalescent plasma not being superior to placebo). These three quantities are similar to the point estimate, 95% con dence interval, and p-value that are generated in frequentist analyses. In fact, point estimates using the likelihood and frequentist approaches are often identical, and the interval estimates are often very similar to 95% con dence intervals. The likelihood ratio (LR) and the p-value, however, are distinct measures of evidence. The LR is a ratio: the density of the trial data if the treatment is effective (alternative hypothesis) divided by the density of the trial data if the treatment is not effective (null hypothesis). A LR of 1 indicates the data are neutral; neither the alternative hypothesis nor null hypothesis is supported more strongly than the other. A large LR is evidence in support of the treatment being effective. An LR less than one is evidence that the treatment is harmful. In this trial, a LR ≥ 7 in favor of the intervention group is considered su cient evidence to assert that the treatment is bene cial.
The likelihood approach is different than using p-values as the level of evidence because the p-value compares what actually happened in the trial to what might have happened if the trial were repeated in nitely and the null hypothesis were true. Because it is impossible to compute what might have happened if the rules for decision making are not fully prede ned, using a p-value for decision making is not well suited for a trial like this in which pandemic circumstances prompt urgent design changes. The LR approach on the other hand, is based on a relative likelihood of observed outcomes under two competing models at the same point in time, making it especially appropriate for settings where prespeci cation of the timing or frequency of sequential analyses is not possible.

Interim analyses
The anticipated sample size is 1,000 enrolled patients. The trial includes three planned interim analyses, to be conducted after primary outcome data collection is completed for 150, 450, and 750 study participants. Additional interim analyses may be called at any time by the DSMB based on changes in the pandemic and/or emerging data on COVID-19 convalescent plasma. Adverse events, safety outcomes, protocol deviations, and the primary endpoint are presented to the DSMB at each interim analysis.
Additionally, as a safety evaluation, the difference in mortality risk between groups is calculated, and the one-sided hypothesis that mortality risk in the intervention arm exceeds the mortality risk in placebo will be compared to the null hypothesis of equal mortality risk. The trial will be stopped for safety if the likelihood ratio for mortality exceeds any of the following thresholds, suggesting increased mortality with convalescent plasma: rst interim analysis, LR 6.3 (which corresponds to a p-value of approximately 0.0275); second interim analysis, LR 4.0 (which corresponds to a p-value of approximately 0.0479); third interim analysis, LR 3.3 (which corresponds to a p-value of approximately 0.0612). These thresholds result in a 0.1 trial-wise risk of stopping the trial early for mortality if mortality were truly equivalent in the intervention and control groups. There are no pre-speci ed stopping rules for e cacy.

Primary analysis of the primary outcome
The primary analysis will be intention-to-treat, with each randomized patient analyzed according to the randomized treatment assignment (convalescent plasma vs. placebo) regardless of the treatment received. The main result will be an estimate of the treatment effect odds ratio, its likelihood ratio when compared to the null, and the corresponding 1/7 likelihood support interval, all of which will be estimated from a cumulative probability ordinal regression model (CPM) with logit link. The marginal likelihood function for the treatment effect parameter will be the asymptotic regression coe cient distribution; speci cally, it will be the normal distribution density function with mean and standard deviation equal to the regression estimates. An odds ratio <1.0 indicates more favorable results on the COVID 7-point Ordinal Clinical Progression Outcomes Scale in the intervention group compared with the control group.
Likelihood ratios more extreme than 7 will be interpreted as su cient evidence to assert e cacy.
The primary model will adjust for the following six baseline characteristics: age (2 parameters, restricted cubic spline); sex (1 parameter); baseline SOFA score (1 parameter, linear term); baseline COVID-19 7point Ordinal Clinical Progression Outcomes Scale score (possible range:3-6) (2 parameters, quadratic); time from symptom onset to randomization in days (2 parameter, non-linear term); and a site indicator variable (as a random effect).
Additional analyses of the primary outcome A per-protocol analysis of the primary outcome will be performed in which randomized patients who did not receive any volume of the study treatment are excluded.
The impact of convalescent plasma quality, as measured by antibody quanti cation and neutralization, on the primary outcome will be estimated with two ordinal regression models. In the rst, the model will include the same covariates listed for the primary analysis with the addition of a measure of donor plasma binding level (value in MFI obtained using the RBD Luminex based assay (42)). In the second model, a measure of donor plasma neutralization (NT50 value obtained using the VSV-SARS-CoV-2 chimeric virus neutralization assay (33,34)) will be used. Both of these variables of convalescent plasma quality will be included in the models as a restricted cubic spline with three knots to capture potential non-linear associations with the outcome. For observations in the control arm, binding and neutralization values will be set to zero. Studies to evaluate alternative measures of convalescent plasma quality are ongoing and, dependent on the results of those analyses, a different measure of quality may be selected.
The degree to which pre-speci ed baseline variables modify the treatment effect will be examined with tests of statistical interaction in a cumulative probability ordinal regression model. Independent variables will include study group assignment, the potential effect modi er of interest, the interaction between the two, and the same pre-speci ed covariates used in the primary model. Presence of effect modi cation will be assessed by reference to the LR for the interaction term, with values greater than 6 considered to suggest a potential interaction and values greater than 7 considered to con rm an interaction. The baseline variables that will be evaluated for effect modi cation include: baseline recipient (trial participant) serum antibody quanti cation; baseline COVID-19 7-point Ordinal Clinical Progression Outcomes Scale score; baseline SOFA score; location at time of enrollment (ICU/ward); age; race/ethnicity; duration of COVID-19 symptoms prior to randomization (days in linear form); and mechanical ventilation status at baseline.

Sample Size and Power
The operating characteristics of the trial design were estimated by simulating study data to re ect different treatment effect sizes. The simulated study dataset was evaluated according to the stopping rule and analysis plan described above. For each effect size, 1000 simulated datasets were analyzed. A Type I error occurred if the study asserted e cacy when in fact there was no treatment effect. The Type I error rate was calculated as the proportion of simulated studies with no treatment effect in which the error occurred. A Type II error occurred if the study failed to assert e cacy when there was a bene cial treatment effect. For each treatment effect, power was calculated as the proportion of simulated studies that did not result in a Type II error.
The study endpoint for control subjects was simulated to match the outcomes in the control arm of a recent clinical trial. (43) In each simulation setting, the distribution for the treatment arm was calculated by adjusting the control arm outcome distribution according to the setting-speci c treatment effect size and data generation model. These simulations demonstrated that enrollment of 1000 patients (500 patients in the intervention group and 500 patients in the control group) would provide 80% power to detect an adjusted odds ratio of ≤0.73 (Figure 3). Some trials orient the ordinal outcomes scale in the reverse direction, with an odds ratio greater than 1.0 indicating bene t from the intervention. (3,36) With reversal of the ordinal outcomes scale, enrollment of 1000 patients would provide 80% power to detect an adjusted odds ratio ≥1. 37. The simulations also demonstrated that the type I error rate was below 0.05.
Analysis of secondary and safety outcomes Secondary e cacy outcomes will be assessed by intention-to-treat analyses using the same covariables as the primary model for the primary outcome. Safety outcomes will be analyzed in the safety population, classi ed based on receipt of convalescent plasma from the trial vs. those who received placebo from the trial regardless of randomized assignment, without covariable adjustment.
Adjustments will not be made for multiple comparisons.

Discussion
PassITON is an ongoing blinded, placebo-controlled randomized trial evaluating the e cacy of COVID-19 convalescent plasma for the treatment of adults hospitalized with moderate-to-severe acute COVID-19.
The rst patient was enrolled on April 28, 2020 and trial completion is anticipated in 2021.
COVID-19 convalescent plasma has been administered to hundreds of thousands of patients in the US, initially under an EAP (44) and now under EUA. (20) While data from these programs support the safety of convalescent plasma, evidence of e cacy is lacking. PassITON is designed to provide rigorous e cacy data. As such, key design features include: meticulous selection of convalescent plasma with high levels of anti-SARS-CoV-2 antibodies with neutralizing activity; enrollment of a geographically diverse patient population in hospitals across the US; patient-level randomization to COVID-19 convalescent plasma or matching placebo; blinding of participants, investigators and outcome assessors to treatment assignment; and systematic collection of patient-centered outcomes for four weeks following infusion of the study treatment. These characteristics distinguish PassITON from many other COVID-19 convalescent plasma trials which have either reported null ndings (PLACID(24), PlasmAR(25)) or recently stopped for futility.(45, 46) In addition, the rigorous plasma donation and screening program required in PassITON to ensure the use of COVID-19 convalescent plasma with potent neutralizing antibodies has demonstrated important challenges that would need to be overcome to develop a scalable pipeline for supplying neutralizing COVID-19 convalescent plasma if it is found to be an effective therapy. With only approximately 25% of units donated from patients who have recovered from COVID-19 having neutralizing activity, stringent donor screening and antibody quanti cation steps would need to be implemented to ensure the use of effective convalescent plasma.
PassITON evaluates the e cacy of COVID-19 convalescent plasma among hospitalized patients, which is the same population described in the FDA EUA. (20) The e cacy of COVID-19 convalescent plasma among patients with less severe disease and/or who are earlier in their disease course is being evaluated in other trials. (47,48) Convalescent plasma had been used as a therapy for severe viral illnesses for over a century and in hundreds of thousands of COVID-19 patients during the past year. Despite this enthusiastic use of convalescent plasma, its clinical e cacy remains unclear. Effectively managing COVID-19 patients in the current pandemic and developing a robust infrastructure to respond to future viral pandemics requires evidence-based answers to long-standing questions about the e cacy of convalescent plasma.
PassITON will advance our understanding of convalescent plasma, and combined with other work, help inform treatment options for COVID-19 and future pandemics.