Covid-19 living Data

Convalescent plasma vs Standard care/Placebo (RCT)

Hospitalized patients

Studies included but not extracted/included in the analysis: Jalili E,Tanaffos, 2022; Denkinger C M, medrxiv, 2022 ; Thorlacius-Ussing L, Sci Rep, 2022; Villanueva C, medrxiv, 2022 ; Muller-Tidow C, Hemasphere, 2022

FOREST PLOTS -2022-10-20

Studies description

Trial CTRI/2020/04/024775
Publication PLACID - Agarwal A, BMJ (2020) (published paper)
Dates: 2020-04-22 to 2020-07-14
Funding: Public/non profit (Indian Council of Medical Research (ICMR))
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / India Follow-up duration (days): 28
Inclusion criteria	Patients aged at least 18 years who had confirmed covid-19 based on a positive reverse transcriptase polymerase chain reaction (RT-PCR) result for SARSCoV- 2 and had been admitted to the participating hospitals were screened for eligibility. Inclusion criteria were moderate illness with either a partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2) ratio between 200 mm Hg and 300 mm Hg or a respiratory rate of more than 24/min with oxygen saturation (SpO2) 93% or less on room air,17 and availability of a matched donor for convalescent plasma at the point of enrolment.
Exclusion criteria	Pregnant and lactating women, patients with known hypersensitivity to blood products, recipients of immunoglobulin in the past 30 days, patients with conditions precluding infusion of blood products, participants in any other clinical trials, and critically ill patients with PaO2/ FiO2 <200 mm Hg or shock (requiring vasopressors to maintain a mean arterial pressure (MAP) of ≥65 mm Hg or MAP of <65 mm Hg).
Interventions
	Treatment Convalescent plasma two doses of 200 ml, transfused 24 hours apart
	Control Standard care
Participants
	Randomized participants : Convalescent plasma=235 Standard care=229
	Characteristics of participants N= 464 Mean age : NR 354 males Severity : Mild: n=361 / Moderate: n=101 / Severe: n=1 Critical: n=*
Primary outcome
	In the register composite measure of the avoidance of 1. Progression to severe ARDS (P/F ratio 100) or 2. All-cause Mortality at 28 days Timepoint: 28 days from intervention
	In the report The composite measure of progress to severe disease (PaO2/FiO2 ratio <100) any time within 28 days of enrolment or all-cause mortality at 28 days.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to all available versions of the pre-prints and published article, the study registry was used in data extraction and risk of bias assessment.The study achieved the target sample size specified in the trial registry. There is no change from the trial registration in the intervention and control treatments. The primary outcome indicated in registry reflects the primary outcome reported in the paper This study was updated on 03/11/2020 based on the published article.

Trial NCT04356534
Publication AlQahtani M, Sci Rep (2021) (published paper)
Dates: 2020-04-19 to 2020-06-15
Funding: Public/non profit (Ministry of Health Bahrain and the College of Surgeons in Ireland-Bahrain)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Bahrain Follow-up duration (days): 28
Inclusion criteria	(1) signed informed consent (2) aged at least 21 years (3) COVID-19 diagnosis based on polymerase chain reaction (PCR) testing (4) Hypoxia (Oxygen saturation of less than or equal 92% on air, or PO2 < 60mmHg in arterial blood gas, or arterial partial pressure of oxygen (PaO )/fraction of inspired oxygen (FIO) of 300 or less) and patient requiring oxygen therapy (5) pneumonia confirmed by chest imaging.
Exclusion criteria	(1) Patients with mild disease not requiring oxygen therapy (2) Patients with normal CXR or CT scan (3) Patients requiring ventilatory support (invasive or non-invasive) (4) Patients with a negative PCR test for SARS-CoV-2 (5) Patients with a history of allergy to plasma, sodium citrate or methylene blue, or those with a history of autoimmune disease or selective IGA deficiency.
Interventions
	Treatment Convalescent plasma 200 mL infusion over 2 hours on 2 successive days.
	Control Standard care
Participants
	Randomized participants : Standard care=20 Convalescent plasma=20
	Characteristics of participants N= 40 Mean age : NR 32 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=40 Critical: n=0
Primary outcome
	In the register Requirement for invasive ventilation [ Time Frame: through study completion up to 28 days ]
	In the report Requirement for invasive or non-invasive ventilation, and, in patients who required ventilation, the duration of ventilation.
Documents avalaible	Protocol Yes. In English Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published/pre-print article, the study protocol and trial registry were used in data extraction and assessment of risk of bias. No statistical analysis plan was available. There were no substantive differences between the pre-print article, the study protocol and trial registry in terms of procedures, population, treatments and outcomes. The pilot study reached its pre-stated sample size. Adverse events were only reported for the intervention arm. On 18th of May, 2021, this study was updated based on the published report.

Trial NCT04345523
Publication ConPlas-19 - Avendano-Sola C, J Clin Invest (2021) (published paper)
Dates: 2020-04-04 to 2021-02-05
Funding: Public/non profit (Government of Spain, Instituto de Salud Carlos III)
Conflict of interest: No

Trial NCT04425915
Publication COPLA-II trial - Bajpai M, BMJ Open (2022) (published paper)
Dates: 2020-06-14 to 2020-11-17
Funding: No specific funding (The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. )
Conflict of interest: No

Trial ISRCTN85216856
Publication Baldeon ME, Transfus Med (2022) (published paper)
Dates: 2020-05-10 to 2020-10-31
Funding: Public/non profit (Salvar Vidas Ecuador (SalvarVidasEC))
Conflict of interest: No

Methods
	RCT Blinding: triple blinding
	Location : Multicenter / Ecuador Follow-up duration (days): 28
Inclusion criteria	Signed informed consent ≥18 years of age both sexes COVID-19 diagnosis based on: any molecular testing-polymerase chain reaction (RT-PCR), clinical diagnosis or lung imaging tests patients with impairment of previously normal lung function defined with a SaO2 <90% at 0.5FiO2 and/or with an increased O2 need in the previous 24 h upon admission patients with a score of 5–6 on the New Early Warning Scale for COVID-19 patients.
Exclusion criteria	Pregnant or lactating had diagnosis of cancer, HIV infection, superimposed systemic infections, liver failure, renal failure, chronic obstructive pulmonary disease, pulmonary fibrosis, and restrictive pulmonary pathologies had been receiving immunosuppressants for a different condition than SARS-CoV-2 infection were participating in any other clinical trial patients with history of previous blood/derivate transfusion
Interventions
	Treatment Convalescent plasma 5 ml/kg intravenously once-off
	Control Placebo
Participants
	Randomized participants : Convalescent plasma=63 Placebo=95
	Characteristics of participants N= 158 Mean age : NR 107 males Severity : Mild: n=0 / Moderate: n=* / Severe: n=* Critical: n=*
Primary outcome
	In the register Case fatality rate assessed through data collected from the follow-up instrument and medical record at 21 and 28 days
	In the report Survival rate before 28 days since onset of plasma transfusion treatment.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	“In addition to the published article, the study registry was used in data extraction and risk of bias assessment. The protocol and statistical analysis plan were not available. There is no change from the trial registration in the intervention and control treatments. The primary outcome in the article reflected that in the registry. The study (n=158) did not achieve its target sample size (n=200) as it was suspended early due to futility after a planned interim analysis."

Trial NCT04397757
Publication PennCCP2 - Bar KJ, J Clin Invest (2021) (published paper)
Dates: 2020-05-18 to 2021-01-08
Funding: Public/non profit (University of Pennsylvania. There was no commercial support for this trial.)
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / USA Follow-up duration (days): 60
Inclusion criteria	Hospitalized adults RT-PCR–confirmed SARS-CoV-2 infection radiographic documentation of pneumonia Abnormal respiratory status, defined as room air saturation of oxygen (SaO2) less than 93%, or requiring supplemental oxygen, or tachypnea with a respiratory rate greater than or equal to 30
Exclusion criteria	Contraindication to transfusion Participating in other clinical trials of investigational COVID-19 therapy Clinical suspicion that the etiology of acute illness was primarily due to a condition other than COVID-19 If ABO-compatible CCP was unavailable.
Interventions
	Treatment Convalescent plasma Up to 2 units intravenously once-off on day 1
	Control Standard care
Participants
	Randomized participants : Convalescent plasma=41 Standard care=39
	Characteristics of participants N= 80 Mean age : NR 36 males Severity : Mild: n=4 / Moderate: n=42 / Severe: n=33 Critical: n=0
Primary outcome
	In the register 1)Participants with serious adverse events. [ Time Frame: Up to 29 days from treatment ]; 2)Cumulative incidence of serious adverse events (SAEs) at Study Day 29. Comparison of clinical severity score between patients on the experimental versus control arms; [ Time Frame: Up to 29 days from treatment ]
	In the report 1) Clinical severity score (8-point WHO ordinal score); 2) cumulative incidence of serious adverse events (SAEs) at Day 29
Documents avalaible	Protocol NR Statistical plan Yes Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the statistical analysis plan, supplementary material, study registry and data from contact with authors were used in data extraction and risk of bias assessment. No protocol was available. There is no change from the trial registration in the intervention and control treatments. Only 1 of the 2 primary outcomes indicated in the registry was reported as a primary outcome in the paper, the other was a secondary outcome. The study (n=80) achieved the target sample size (n=80) specified in the trial registry." This study was updated on May 9th, 2022 with data obtained from contact with the authors. This was study was updated on September 14th, 2022 with data extracted from the registry.

Trial NCT04803370
Publication Bargay-Lleonart J, J Clin Med (2022) (published paper)

Funding: Public/non profit (Health Research Institute of the Balearic Islands)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Spain Follow-up duration (days): 21
Inclusion criteria	Age greater than or equal to 18 years male or female hospitalized in a COVID-19 area (non-intensive care where COVID-19 patients were hospitalized for specific management SARS-CoV-2 on nasopharyngeal swabs at the time of the screening presence of respiratory symptoms and/or fever associated with COVID-19, with clinical time evolution equal to or less than 7 days (day 1 being the day of symptom onset, and including day 7) presence of pneumonia on chest X-ray and/or SatO2 < 94% aa Sequential Organ Failure Assessment score (SOFA) < 6 ability to understand the patient information sheet and sign written informed consent accepting the condition of complying with the procedures established in the protocol.
Exclusion criteria	Patients with a previous history of allergic reaction to any blood component pregnant or lactating women patients treated with plasma within 21 days prior to the screening patients with incompatible conditions, e.g., being a participant in other clinical trials.
Interventions
	Treatment Convalescent plasma Two doses of 300 mL intravenously every 24 h on days 1 and 2
	Control Standard care
Participants
	Randomized participants : Convalescent plasma=38 Standard care=17
	Characteristics of participants N= 55 Mean age : NR 33 males Severity : Mild: n=0 / Moderate: n=* / Severe: n=* Critical: n=0
Primary outcome
	In the register WHO clinical progression scale [Time Frame: Day 21]. The scale provides a measure of illness severity across a range from 0 (not infected) to 9 (Mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis, or ECMO)
	In the report Time to recover or achieve clinical improvement, where recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: (1) Not hospitalized, no limitations on activities (Point = 8); (2) not hospitalized, limitation on activities, and/or requiring home oxygen (Point = 7); (3) hospitalized, not requiring supplemental oxygen—no longer requires ongoing medical care (Point = 6)
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the study registry was used in data extraction and risk of bias assessment. The protocol and statistical analysis plan were not available. "The trial was terminated early due to the impossibility of recruitment due to the pandemic". The target sample size was therefore not achieved.

Trial NCT04348656
Publication CONCOR-1 - Begin P, Nat Med (2021) (published paper)
Dates: 2020-05-14 to 2021-01-29
Funding: Public/non profit (Canadian Institutes of Health Research; Ontario COVID-19 Rapid Research Fund; Toronto COVID-19 Action Initiative 2020 (University of Toronto); University Health Network Emergent Access Innovation Fund; University Health Academic Health Science Centre Alternative Funding Plan (Sunnybrook Health Sciences Centre); Ministère de l'Économie et de l'Innovation (Québec); Fond de Recherche du Québec en Santé; Saskatchewan Ministry of Health; University of Alberta Hospital Foundation; Alberta Health Services COVID-19 Foundation Competition; Sunnybrook Health Sciences Centre Foundation; Fondations CHU Ste-Justine; The Ottawa Hospital Academic Medical Organization; The Ottawa Hospital Foundation COVID-19 Research Fund; Fondation du CHUM; Sinai Health System Foundation and McMaster University. These did not have any role in the writing of the manuscript or the decision to submit it for publication. The authors did not receive payments from any pharmaceutical company or other agency to write this article.)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Canada, USA, Brazil Follow-up duration (days): 90
Inclusion criteria	>16 in Canada or >18 years of age in the United States and Brazil admitted to the hospital ward with confirmed COVID-19 required supplemental oxygen availability of ABO-compatible convalescent plasma from donors who had recovered from COVID-19 infection was an eligibility requirement
Exclusion criteria	More than 12 days from the onset of respiratory symptoms imminent or current intubation a contraindication to plasma transfusion a plan for no active treatment
Interventions
	Treatment Convalescent plasma 500 mL IV infusion once-off (or 2 units of 250 mL from 1 or 2 donors)
	Control Standard care
Participants
	Randomized participants : Convalescent plasma=627 Standard care=313
	Characteristics of participants N= 940 Mean age : NR 554 males Severity : Mild: n=0 / Moderate: n=* / Severe: n=* Critical: n=0
Primary outcome
	In the register Intubation or death [Time Frame: Day 30]
	In the report Composite of intubation or death by day 30
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	This trial was terminated early due to futility upon interim analysis. In addition to the preprint, the protocol, statistical analysis plan and study registry were used in data extraction and risk of bias assessment. The study randomized 940 out of the pre-planned sample size of 1200. There are no substantive changes from the registry/protocol in the study population, procedures, intervention and control treatments. The primary outcome indicated in the registry/protocol reflects the primary outcome reported in the paper. Unblinded study. No information on administration in each group of biologics co-interventions of interest. The study reports 4 vs 4 participants of the intention-to-treat population not to be on oxygen at randomization. While mortality (D28) results were based on all cause mortality, mortality (D60 and more) and time to death as well as time to WHO score 7 and above was solely considering in-hospital mortality. The study was updated on September 14th, 2022 with data from the published report.

Trial RBR-7f4mt9f
Publication De Santis GC, Emerg Infect Dis (2022) (published paper)
Dates: 2020-04-14 to 2020-11-30
Funding: Public/non profit (Fundação de Amparo à Pesquisa do Estado de São Paulo)
Conflict of interest: *

Trial NCT04429854
Publication DAWN-plasma trial - Devos T, Eur Respir J (2021) (published paper)
Dates: 2020-05-02 to 2021-01-26
Funding: Public/non profit (Fonds Wetenschappelijk Onderzoek (FWO) [Research Foundation – Flanders]; Belgian Health Care Knowledge Centre (KCE))
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Belgium Follow-up duration (days): 30
Inclusion criteria	Adult (≥18 years) hospitalised laboratory or radiological confirmed COVID-19 Illness of any duration at least one of the following: a) Radiographic infiltrates by imaging (chest X-ray, CT scan or other), or b) Abnormalities on clinical assessment (evidence of rales/crackles on exam) and oxygen saturation (SpO2) ≤ 94% on room air, or c) Requiring supplemental oxygen.
Exclusion criteria	Patients receiving mechanical ventilation upon assessment or a therapy restriction code excluding mechanical ventilation and/or endotracheal intubation pregnancy or lactation documented previous grade 3 allergic reaction to plasma transfusions treatment with rituximab or another anti-CD20 monoclonal antibody during the past year Any medical condition which would impose an unacceptable safety hazard by participation to the study, as deemed by the investigator.
Interventions
	Treatment Convalescent plasma Two units (200-250 mL) intravenously within 12 hours after randomisation, with a second administration of two units 24-36 hours after the first administration (81% from donors with neutralising antibody titres ≥ 1/320; NT50).
	Control Standard care
Participants
	Randomized participants : Convalescent plasma=326 Standard care=163
	Characteristics of participants N= 489 Mean age : NR 332 males Severity : Mild: n=57 / Moderate: n=* / Severe: n=* Critical: n=0
Primary outcome
	In the register Patients requiring mechanical ventilation or death [ Time Frame: No mechanical ventilation at day 15 after hospitalization.] Primary outcome of the study is the number of patients alive without mechanical ventilation at day 15 after hospitalization.
	In the report Number and proportion of patients alive without mechanical ventilation at Day 15.
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: N
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the protocol, statistical analysis plan and study registry were used in data extraction and risk of bias assessment. There is no change from the trial registration in the intervention and control treatments. The registry primary outcome reflects the reported primary outcome. The study (n=489) achieved the target sample size specified in the paper (n=483).

Trial NCT02735707
Publication REMAP-CAP - Estcourt L, JAMA (2021) (published paper)
Dates: 2020-05-05 to 2021-01-18
Funding: Mixed (PREPARE consortium by the European Union; Australian National Health and Medical Research Council; Australian Medical Research Future Fund; New Zealand Health Research Council; Canadian Institutes of Health Research COVID-19 Rapid Research Funding; Canadian Institute of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant; NIHR; UK NIHR; NIHR Imperial Biomedical Research Centre; Health Research Board of Ireland; UPMC Learning While Doing Program; Translational Breast Cancer Research Consortium; Pittsburgh Foundation; French Ministry of Health; Minderoo Foundation; Wellcome Trust Innovations Project; Australian government; DHSC; EU SoHo Grants)
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Australia, Canada, UK, USA Follow-up duration (days): 90
Inclusion criteria	Patients aged 18 years or older confirmed SARS-CoV-2 infection admitted to hospital classified as moderately or severely ill were eligible for enrollment in the Covid-19 Immunoglobulin Domain, equivalent to severely or critically ill respectively, as per the World Health Organization (WHO) case definitions.
Exclusion criteria	Presumption that death was imminent with lack of commitment to full support participation in REMAP-CAP in the prior 90 days known hypersensitivity to convalescent plasma objection to receiving plasma products previous history of transfusion-related acute lung injury (TRALI) and more than 48h elapsed since ICU admission or 14 days since hospital admission.
Interventions
	Treatment Convalescent plasma total volume 550+/-150 ml IV infusion. First unit on D1, second unit a minimum of 12 hours later, if no serious adverse reaction to transfusion
	Control Standard care
Participants
	Randomized participants : Convalescent plasma=1084 Standard care=916
	Characteristics of participants N= 2000 Mean age : NR 1345 males Severity : Mild: n=0 / Moderate: n=* / Severe: n=1336 Critical: n=648
Primary outcome
	In the register 1. All-cause mortality [ Time Frame: Day 90 ] 2. Days alive and not receiving organ support in ICU [ Time Frame: Day 21 ] Primary end-point for patients with suspected or proven COVID-19 pandemic infection
	In the report Respiratory and cardiovascular organ support-free days up to day 21
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Low
General comment	In addition to the published article, the pre-print, study registry and protocol were used in data extraction and risk of bias assessment. The report contains convalescent plasma vs mask data from the Immunoglobulin domain of the REMAP-CAP clinical trial (an international, adaptive platform trial). This arm of the trial was terminated due to futility. Quote: "At a scheduled adaptive analysis, the statistical trigger for futility in critically ill participants with Covid-19 was met (posterior probability of futility 96.4%, (OR 0.95, 95% Credible Interval (CrI) 0.73 to 1.23). Assignment to this domain closed on January 11, 2021 for critically ill participants (randomization continued for participants who were not critically ill). After announcement of the preliminary RECOVERY trial results on January 15,2021, the ITSC halted recruitment to all patients within the domain" There was some discrepancy between the report and the protocol as it pertains to time to death. The protocol pre-specifies this outcome as "ICU mortality censored at 90 days". There were no important changes from the trial registration in the population, intervention, or control treatments. Some outcomes from the registry are not reported in the paper (e.g., All cause mortality) and some outcomes in the report were not specified in the registry (e.g., Serious adverse events). Mortality extracted is in-hospital mortality. Critically ill participants (using WHO definitions of severity) comprised the main analysis, while severe participants were used for borrowing in statistical models. The study was updated on November 11th, 2021 with data from the peer-reviewed publicaiton.

Trial NCT04405310
Publication Fernandez-Sanchez V, Research Square (2022) (preprint)
Dates: 2020-05-20 to 2020-10-10
Funding: Public/non profit (CEMEVAV (Centro Medico Naval, Naval Medical Center))
Conflict of interest: No

Methods
	RCT Blinding: double blinding
	Location : Multicenter / Mexico Follow-up duration (days): 21
Inclusion criteria	Adults 18 to 70 years of age diagnosis of COVID-19 confirmed by RT-PCR Hscore ≥169 points severe acute hypoxemia with SpO2 <90% on room air and PaO2 /FiO2 <300 mmHg Meeting imaging criteria for SARS-CoV-2 stage II and III pneumonia (plain chest CT scan or plain chest X-ray) requirement for supplemental oxygen either via face mask plus reservoir bag, high-flow nasal prongs or advanced airway management, and invasive mechanical ventilatory support C reactive protein (CRP) value increased by 3.5 the baseline or greater than 18 mg/dL Stage II was defined as evidence of lower airway disease, either by clinical assessment or imaging, and oxygen saturation (SpO2) ≥94%. Stage III was defined as a respiratory rate >30 breaths per minute, SpO2 <94%, ratio between the arterial partial pressure of oxygen and the fraction of inspired oxygen (PaO2 /FiO2) <300 mmHg, or pulmonary infiltrates >50%.
Exclusion criteria	Patient has no interest in participating in the trial bilateral pulmonary infiltrate related to heart failure or other cause of water overload Virus positive respiratory viral panel other than COVID-19 History of allergy to plasma, sodium citrate, or methylene blue Patients with a history of autoimmune diseases or selective IgA insufficiency Those patients who are participating in other protocols.
Interventions
	Treatment Convalescent plasma 300 mL/day intravenously, on day one and day three
	Control Placebo 300 mL of 20% albumin in Hartman's solution intravenously on day one and day three
Participants
	Randomized participants : Placebo=11 Convalescent plasma=32
	Characteristics of participants N= 43 Mean age : NR 0 males Severity : Mild: n=0 / Moderate: n=* / Severe: n=* Critical: n=15
Primary outcome
	In the register Death [ Time Frame: 15 days ] any cause
	In the report Survival at 15 and 21 days
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	“In addition to the pre-print article, the prospective study registry was used in data extraction and risk of bias assessment. The protocol and statistical analysis plan were not available. No outcome is defined as the primary outcome in the article and the mortality outcome reported (to 21 days) has a different timepoint from the primary outcome in the registry (mortality at day 15). The pilot study (n=42) did not achieve the target sample size specified in the trial registry (n=80)."

Trial NCT04342182
Publication Gharbharan A, Nat Commun (2021) (published paper)
Dates: 2020-04-08 to 2020-06-14
Funding: Mixed (The Erasmusfoundation, Ypsilo and Health Holland)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Netherlands Follow-up duration (days): 60
Inclusion criteria	Eligible patients were at least 18 years, admitted to a study site for COVID-19 and had clinical COVID-19 disease proven by a positive SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) test in the previous 96 hours.
Exclusion criteria	Patients with a documented IgA deficiency or on mechanical ventilation for >96 hours were excluded.
Interventions
	Treatment Convalescent plasma 300 mL IV on the day of inclusion. A second dose could be administered after five days.
	Control Standard care
Participants
	Randomized participants : Convalescent plasma=43 Standard care=43
	Characteristics of participants N= 86 Mean age : NR 62 males Severity : Mild: n=0 / Moderate: n=* / Severe: n=* Critical: n=13
Primary outcome
	In the register Overall mortality [ Time Frame: until hospital discharge or a maximum of 60 days whichever comes first ]
	In the report The primary endpoint of the study was overall mortality until discharge from the hospital or a maximum of 60 days after admission whichever came first.
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to all available versions of the publication/pre-print, the study registry, protocol, and statistical analysis plan were used in data extraction and risk of bias assessment. The April 15th update of the registry (start of trial April 8th, 2020. Follow-up 15 days) was used. Safety outcomes were specified after this but that was considered to be a retrospective update to the registry to be utilized for the risk of bias domain 5. The protocol was also very retrospective (May 11th, 2020). There is no change from the trial registration in the intervention and control treatments. Some pre-specified secondary outcomes and exclusion criteria were not included in the pre-print/publication. According to information on 'Acquisition of patients' in the supplementary file (pre-print), the eligibility criteria was adjusted during recruitment. Quote: "After the first 63 patients these criteria were modified to also include the exclusion criteria known IgA deficiency and >96 hours on invasive ventilation at time of screening." On 2nd of May, 2021, this study was updated based on the published report.

Trial NCT04600440
Publication Holm K, BMC Res Notes (2021) (published paper)
Dates: 2020-06-01 to 2021-01-30
Funding: Public/non profit (Skåne Region)
Conflict of interest: No

Trial NCT04381936; EudraCT 2020-001113-21; ISRCTN5018967
Publication RECOVERY-CP - Horby P, Lancet (2021) (published paper)
Dates: 2020-05-28 to 2021-01-15
Funding: Public/non profit (UK Research and Innovation (Medical Research Council) and National Institute of Health Research )
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / UK Follow-up duration (days): 28
Inclusion criteria	Hospitalised patients any age clinically suspected or laboratory-confirmed SARS-CoV-2 infection no medical history that might, in the opinion of the attending clinician, put them at significant risk if they were to participate in the trial.
Exclusion criteria	For some patients, convalescent plasma was either declined, unavailable at the trial site at the time of enrolment, or considered in the opinion of the attending doctor to be definitely contraindicated (e.g. known moderate or severe allergy to blood components or unwilling to receive a blood product). These patients were ineligible for randomisation to the comparison of convalescent plasma versus usual care.
Interventions
	Treatment Convalescent plasma 275 ml (+/-75 ml) IV infusion; two doses at least 12 hours apart (D1 and D2)
	Control Standard care
Participants
	Randomized participants : Standard care=5763 Convalescent plasma=5795
	Characteristics of participants N= 11558 Mean age : NR 7430 males Severity : Mild: n=897 / Moderate: n=* / Severe: n=* Critical: n=617
Primary outcome
	In the register All-cause mortality [Time Frame: Within 28 days after randomisation].
	In the report 28-day all-cause mortality
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to all available versions of the published/pre-print article, the study registries, statistical analysis plan, protocol and supplementary appendix were used in data extraction and risk of bias assessment. This study reported here is part of the RECOVERY trial (an investigator-initiated, individually randomized, controlled, open-label, adaptive platform trial to evaluate the effects of potential treatments in patients hospitalized with COVID-19. The trial was conducted at 176 National Health Service (NHS) hospital organizations in the United Kingdom). There were no substantive differences in study procedures, population, interventions and outcomes between the pre-print article and the trial registries, study protocol and statistical analysis plan. The study achieved its pre-stated sample size. The study arm was terminated early due to insufficient efficacy. Enrolment was closed on 15th January 2021 and preliminary results made available. Quote: "On 7th January 2021, the independent data monitoring committee (DMC) conducted a routine review of the data and recommended that the chief investigators pause the recruitment to the convalescent plasma comparison in those patients receiving invasive mechanical ventilation (including extracorporeal membrane oxygenation) at the time of randomisation. At the same time, the DMC recommended that recruitment to the convalescent plasma comparison continue for all other eligible patients. On 14th January 2021, the DMC conducted another routine review of the data and notified the chief investigators that there was no convincing evidence that further recruitment would provide conclusive proof of worthwhile mortality benefit either overall or in any pre-specified subgroup. The DMC therefore recommended that recruitment to the convalescent plasma portion of the study should cease and follow-up be completed. Enrolment of patients to the convalescent plasma group was closed on 15th January 2021 and the preliminary result for the primary outcome was made public." On 18th of May, 2021, this study was updated based on the published report.

Trial NCT04542941
Publication Kirenga B, BMJ Open Respir Res (2021) (published paper)
Dates: 2020-09-23 to 2020-12-02
Funding: Public/non profit (Government of Uganda through the Makerere University Research and Innovations Fund)
Conflict of interest: No

Trial NCT04433910; EudraCT 2020-001310-38
Publication CAPSID - Koerper S, J Clin Invest (2021) (published paper)
Dates: 2020-08-30 to 2020-12-24
Funding: Public/non profit (Bundesministerium fuer Gesundheit (German Federal Ministry of Health))
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Germany Follow-up duration (days): 60
Inclusion criteria	SARS-CoV-2 infection confirmed by PCR (bronchoalveolar lavage, sputum, nasal and/or pharyngeal swap) age ≥ 18 years and ≤ 75 years severe disease defined by at least one of the following: a) respiratory rate ≥ 30 breaths / minute under ambient air b) requirement of any type of ventilation support (defined as supplemental oxygen or non-invasive ventilation or invasive ventilation or ECMO) c) needs treatment on ICU written informed consent by patient or representative.
Exclusion criteria	Accompanying diseases other than COVID-19 with an expected survival time of less than 12 months previous treatment with any SARS-CoV-2-convalescent plasma in the opinion of the clinical team, progression to death is imminent and inevitable within the next 48 hours, irrespective of the provision of treatment Interval > 72 hours since start of mechanical ventilation not considered eligible for extracorporeal oxygenation support chronic obstructive lung disease (COPD), stage 4 lung fibrosis with usual interstitial pneumonia pattern in CT and severe emphysema chronic heart failure NYHA ≥ 3 and/or pre-existing reduction of left ventricular ejection fraction to ≤ 30% shock of any type requiring ≥ 0.5 μg/kg/min noradrenaline (or equivalent) or requiring more than two types of vasopressor medication for more than 8 hours liver cirrhosis Child C liver failure: bilirubin > 5 x upper limit of normal (ULN) and elevation of ALT /AST (at least one >10 x ULN) any history of adverse reactions to plasma proteins known deficiency of immunoglobulin A pregnancy breastfeeding women volume overload until sufficiently treated participation in another clinical trial with an investigational medicinal product.
Interventions
	Treatment Convalescent plasma 1 transfusion unit on days 1, 3 and 5. Median total volume = 846 ml (IQR 824-855 ml)
	Control Standard care
Participants
	Randomized participants : Convalescent plasma=53 Standard care=52
	Characteristics of participants N= 105 Mean age : NR 77 males Severity : Mild: n=7 / Moderate: n=13 / Severe: n=49 Critical: n=36
Primary outcome
	In the register Composite endpoint of survival and no longer fulfilling criteria of severe COVID-19. [ Time Frame: Day 21 ]
	In the report Dichotomous composite outcome of survival and no longer requiring ventilation support or ICU treatment and no tachypnea (i.e., respiratory rate <30 breaths/minute) on day 21.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published journal and pre-print articles, the trial registry and supplementary appendices (including statistical analysis plan) were used in data extraction and assessment of risk of bias. No protocol was available. There were no substantive differences between the prospective registry and the publication in population, procedures or interventions. The primary outcome indicated in registry reflects the primary outcome reported in the paper. Some outcomes from the registry are not reported in the paper. The analysis for this report is based on an interim data-cut off on April 28, 2021. The study achieved its targeted sample size. This trial was updated on October 6th, 2021 with data from the peer-reviewed journal publication.

Trial NCT04345991
Publication CORIPLASM - Lacombe K, Vox Sang (2022) (unpublished results)
Dates: 2020-04-16 to 2021-04-21
Funding: Public/non profit (Programme Hospitalier de Recherche Clinique ; Fondation pour la Recherche Médicale ; Sorbonne Université Paris )
Conflict of interest: *

Trial ChiCTR2000029757
Publication Li L, JAMA (2020) (published paper)
Dates:

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Brazil Follow-up duration (days): 60
Inclusion criteria	Diagnosis of COVID-19 based on RT-PCR results respiratory distress (oxygen saturation at room air <93%, or arterial partial pressure of oxygen/fraction of inspired oxygen <300, or requiring mechanical ventilation) resulting from pneumonia being within 10 days of initial symptoms age 18–80 years signed written informed consent by the patient or legal representative
Exclusion criteria	History of previous severe allergy to plasma transfusion severe congestive heart failure terminal renal failure hepatic cirrhosis any severe illness expected to confer a short life expectancy participation in any other clinical trial with therapeutic intervention immunosuppression
Interventions
	Treatment Convalescent plasma 300 mL by infusion twice a day for 3 days (or 200 mL/400 mL)
	Control Standard care
Participants
	Randomized participants : Convalescent plasma=37 Standard care=73
	Characteristics of participants N= 110 Mean age : NR 67 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=17 Critical: n=90
Primary outcome
	In the register Survival rate in each group on day 30 of orotracheal intubation or diagnosis of respiratory failure
	In the report Death rate at days 30 and 60
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	The published paper and retrospective trial registry were used in data extraction and risk of bias assessment. Neither protocol nor statistical analysis plan was available. The 30-day primary outcome in the article reflected that in the registry; the longer primary outcome timepoint of 60 days was not included in the registry. The trial terminated early due to difficulties recruiting as the number of new cases substantially decreased. Consequently, the study (n = 110) did not quite achieve the target sample size planned (n = 120).

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Sweden Follow-up duration (days): 28
Inclusion criteria	Admitted to the hospital nasopharyngeal swab positive for SARS-CoV-2 in RT-PCR no later than 4 days prior to inclusion need for supplemental oxygen treatment to keep peripheral oxygen saturation > 93% written informed consent.
Exclusion criteria	Age below 18 a habitual oxygen saturation below 94% inability to give informed consent severe immunosuppression.
Interventions
	Treatment Convalescent plasma 200-250 mL/day intravenously over 30 min for three consecutive days.
	Control Standard care
Participants
	Randomized participants : Convalescent plasma=18 Standard care=15
	Characteristics of participants N= 33 Mean age : NR 19 males Severity : Mild: n=0 / Moderate: n=* / Severe: n=* Critical: n=*
Primary outcome
	In the register Number of days in need of oxygen [ Time Frame: 28 days ]
	In the report Number of days within 28 days after inclusion with a need for oxygen therapy to keep an oxygen saturation above 93%.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the trial registry (retrospective) and supplementary appendix were used in data extraction and assessment of risk of bias. Neither protocol nor statistical analysis plan was available. The primary outcome in the article reflects that in the registry. The longest follow up in the registry (3 months for two secondary outcomes, mortality and discharge) was not reported, but this change was declared in the article. Recruitment was terminated because studies were published that indicated that convalescent plasma was ineffective in the type of patients included in the study per inclusion and exclusion criteria and as a result of vaccination of the elderly.

Methods
	RCT Blinding: Unblinded
	Location : Single center / Uganda Follow-up duration (days): 28
Inclusion criteria	Adults with documented laboratory RT PCR confirmed SAR-CoV-2 infection able to provide informed consent.
Exclusion criteria	Prior diagnosis of IgA deficiency Inability to return for post discharge follow up
Interventions
	Treatment Convalescent plasma 1.4–2 mL/min over 2-3 hours, repeated 3 hours later
	Control Standard care
Participants
	Randomized participants : Convalescent plasma=69 Standard care=67
	Characteristics of participants N= 136 Mean age : NR 97 males Severity : Mild: n=57 / Moderate: n=35 / Severe: n=31 Critical: n=0
Primary outcome
	In the register Time to viral clearance (RT-PCR negativity) [ Time Frame: 28 days ]
	In the report Time to viral clearance, defined by two consecutive negative SARS-CoV-2 RT-PCR test results.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the prospective registry and supplemental appendices were used in data extraction and assessment of risk of bias. Neither protocol nor statistical analysis plane was available. The reported primary outcome reflected that in the registry. One secondary outcome (clinical status on the modified WHO Ordinal Clinical Scale for clinical improvement) was not included in the registry as “improvement” but reported as deterioration (≥1-point increase in scale). The study achieved its target sample size.

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / France Follow-up duration (days): 28
Inclusion criteria	Patients included in the CORIMUNO-19 cohort Onset of COVID19 functional signs <8 days (plasma transfusion may occur up to day 10 of onset) Mild severity as described in the WHO scale
Exclusion criteria	Pregnancy Current documented and uncontrolled bacterial infection Prior severe (grade 3) allergic reactions to plasma transfusion
Interventions
	Treatment Convalescent plasma 2 units/day IV for 2 days
	Control Standard care
Participants
	Randomized participants : Convalescent plasma=60 Standard care=60
	Characteristics of participants N= 120 Mean age : NR 76 males Severity : Mild: n=0 / Moderate: n=120 / Severe: n=0 Critical: n=0
Primary outcome
	In the register 1. Survival without needs of ventilator utilization or use of immunomodulatory drugs (other than steroids) [ Time Frame: At day 14 after randomization ]; 2. WHO progression scale ≥6 [ Time Frame: at day 4 of randomization ]
	In the report The proportion of patients with WHO CPS greater than 5 on the 10-point scale on day 4 and survival without ventilation or additional immunomodulatory treatment by day 14
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	The conference abstract and trial registry were used in data extraction and risk of bias assessment. The CORIPLASM study is a randomized adaptive trial, nested within the CORIMUNO-19 cohort. The study achieved the target sample size specified in the trial registry (n=120). There is no change from the trial registration in the intervention and control treatments. The registry primary outcome reflects the reported primary outcome. Some outcomes from the registry are not reported in the abstract (e.g., Time from randomization to discharge). Adverse events are not reported. On Oct 5, 2022, this study was updated with information provided by contact with authors. Of note, all time to event outcomes have been adjusted for age and centre.