Covid-19 living Data

Convalescent plasma vs Standard care/Placebo (RCT)

Mild outpatients

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 -2022-11-17

Studies description

Trial NCT04621123
Publication Alemany A, Lancet Respir Med (2022) (published paper)
Dates: 2020-11-10 to 2021-07-28
Funding: Mixed (The Fight AIDS and Infectious Diseases Foundation (Badalona, Spain) with funding from the pharmaceutical company, Grifols Worldwide Operations (Dublin, Ireland); the Crowdfunding campaign, YoMeCorono; the Hospital Universitari Germans Trias i Pujol, and Banc de Sang i Teixits de Catalunya.)
Conflict of interest: No

Methods
	RCT Blinding: double blinding
	Location : Multicenter / Spain Follow-up duration (days): 60
Inclusion criteria	50 years or older non-hospitalised (not admitted to hospital) with mild-to-moderate COVID-19 confirmed SARS-CoV-2 infection, with a positive PCR or validated antigen rapid test result received no more than 5 days before randomization symptom onset no more than 7 days before randomization Mild and moderate COVID-19 were defined according to international guidelines: patients with fever, cough, sore throat, malaise, headache, and muscle pain were considered to have mild COVID-19, whereas evidence of lower respiratory disease by clinical assessment or imaging and a saturation of oxygen 94% or more on room air was considered moderate COVID-19.
Exclusion criteria	Severe COVID-19 required hospitalisation for any cause history of a previous SARS-CoV-2 infection received one or two doses of a COVID-19 vaccine contraindications to the investigational product increased thrombotic risk history of clinically significantly abnormal liver function (eg, Child-Pugh C) or chronic kidney disease stage 4 or worse pregnant, breastfeeding, or planning a pregnancy during the study period.
Interventions
	Treatment Convalescent plasma 250–300 mL intravenously once-off
	Control Placebo
Participants
	Randomized participants : Convalescent plasma=188 Placebo=188
	Characteristics of participants N= 376 Mean age : NR 203 males Severity : Mild: n= 366/ Asymptomatic: n=0
Primary outcome
	In the register Hospitalization rate (safety and efficacy) [ Time Frame: Day 28 ]; SARS-CoV-2 viral load (safety and efficacy) [ Time Frame: Day 7 ]
	In the report Incidence of hospitalisation within 28 days from baseline; change in viral load in nasopharyngeal swabs from baseline to day 7.
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 prospective trial registry, protocol, statistical analysis plan and supplementary appendices were used in data extraction and assessment of risk of bias. There is no change from the trial registration in the intervention and control treatments. The primary outcomes reported in the article reflect those in the registry. Recruitment to the trial was terminated on the advice of the data and safety monitoring board because more than 85% of the target population had been vaccinated (an exclusion criterion) and thus the study (n= 376) did not achieve the target sample size (n=474). This study was updated on May 11th, 2022 with data acquired from contact with authors.

Trial NCT04355767
Publication SIREN-C3PO - Korley F, N Engl J Med (2021) (published paper)
Dates: 2020-08-11 to 2021-02-28
Funding: Public/non profit (National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health; the Biomedical Advanced Research and Development Authority; the Operation Warp Speed interagency program.)
Conflict of interest: Yes

Methods
	RCT Blinding: single blinding
	Location : Multicenter / USA Follow-up duration (days): 30
Inclusion criteria	SARS-CoV-2 infection as confirmed by nucleic acid assay onset of symptoms within 7 days before enrollment either 50 years of age or older or had one or more risk factors for disease progression (hypertension diabetes coronary artery disease chronic lung disease chronic kidney disease immunosuppression sickle cell disease, and body mass index >30) written informed consent.
Exclusion criteria	Younger than 18 years of age prisoners or wards of the state patients who were deemed to have an inability to complete follow-up assessments history of adverse reactions from blood-product transfusion received any blood product within the past 120 days not eligible to receive up to 250 ml of fluid received another investigational treatment for Covid-19, including anti–SARS-CoV-2 monoclonal antibodies or vaccination.
Interventions
	Treatment Convalescent plasma 1 unit ABO-compatible convalescent plasma over ≥30 minutes, once-off
	Control Placebo
Participants
	Randomized participants : Convalescent plasma=257 Placebo=254
	Characteristics of participants N= 511 Mean age : NR 237 males Severity : Mild: n= */ Asymptomatic: n=0
Primary outcome
	In the register Number of patients with disease progression [ Time Frame: 15 days ]. Disease progression defined as death or hospital admission or seeking emergency or urgent care within 15 days of randomization.
	In the report Disease progression within 15 days after randomization, which was a composite of hospital admission for any reason, seeking emergency or urgent care, or death without hospitalization.
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	In addition to the published article, the prospective registry, protocol and statistical analysis plan were used in data extraction and assessment of risk of bias. The primary and secondary outcomes in the article reflect those in the registry. Safety outcomes were not included in the registry, but were included in the protocol. Trial inclusion criteria relating to risk factors for severe disease changed slightly over the course of the study, informed by evolving understanding of the disease. Recruitment to the trial was stopped after the second planned interim analysis, which indicated the pre-specified threshold for futility had been reached, and so the study did not achieve its target sample size. This study was updated on September 8th, 2022 with data extracted from the registry.

Trial NCT04589949, NCT04621123
Publication COMPILE home - Millat-Martinez P, Nat Commun (2022) (published paper)
Dates: 2020-11-01 to 2021-07-13
Funding: Mixed (ZONMW (the Netherlands), SUPPORT-E, YoMeCorono, The Fight AIDS and Infectious Diseases Foundation with funding from the pharmaceutical company Grifols S.A.)
Conflict of interest: No

Methods
	RCT Blinding: triple blinding
	Location : Multicenter / Netherlands, Spain Follow-up duration (days): 28
Inclusion criteria	Participant of a trial that joined the COMPILEhome consortium Confirmed COVID-19 diagnosis by a diagnostic PCR or antigen test Neither hospitalized nor at the emergency room department of a hospital before or at the time of randomization Symptomatic with illness onset ≤7 days at the time of screening for the study Age 50 or older Trials had to be approved by the institutional review boards, and competent authorities of the countries involved All patients gave written informed consent
Exclusion criteria	Life expectancy <28 days in the opinion of the treating physician (CoV-Early only) Unable to provide written informed consent History of allergic reactions to blood or plasma products or methylene blue Known IgA deficiency History of previous confirmed SARS-CoV-2 infection, significantly abnormal liver function (Child Pugh C), CKD ≥ stage 4, or need of dialysis treatment, pre-existing condition that increases risk of thrombosis (COnV-ert only)
Interventions
	Treatment Convalescent plasma 200-300 mL IV infusion single dose
	Control Placebo Non-convalescent plasma (CoV-Early) or 0.9% saline solution (COnV-ert)
Participants
	Randomized participants : Convalescent plasma=398 Placebo=399
	Characteristics of participants N= 797 Mean age : NR 522 males Severity : Mild: n= 797/ Asymptomatic: n=0
Primary outcome
	In the register CoV-Early trial: Highest disease status [ Time Frame: 28 days following transfusion of convP or FFP ] Highest disease status on the 5-point ordinal disease severity scale in the convP group will be compared with the FFP group; COnV-ert trial: 1) Hospitalization rate (safety and efficacy) [ Time Frame: Day 28 ] Assess the therapeutic potential of early administration of convalescent MBT plasma in reducing the rate of hospitalization in non-hospitalised mild or moderate COVID-19 patients; 2)SARS-CoV-2 viral load (safety and efficacy) [ Time Frame: Day 7 ] Assess the therapeutic potential of early administration of convalescent MBT plasma in reducing SARS-CoV-2 viral load at day 7, measured by quantitative RT-PCR (RT-qPCR) in non-hospitalised mild or moderate COVID-19 patients.
	In the report A 5-point disease severity scale (fully recovered by day 7 or not, hospital or ICU admission and death) and a composite of hospitalization or death.
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 final rerpot, the pre-print article, the trial registries, the protocol and supplementary appendices were used in data extraction and assessment of risk of bias. The article reports the results of two similar trials (CoV-Early and COnV-ert), which started to pool outcome data when less than 20% of their target sample sizes had been randomized, and whose study teams agreed upon a minimal set of data required to analyze the primary and secondary endpoints. The co-primary outcomes in the article reflect the primary outcome in one trial registry and a secondary outcome in the other. The trials (n = 797) did not achieve their combined target sample sizes (n = 1,164) due to early termination of recruitment because of increasing uptake of vaccinations and recommendations for use of monoclonal antibodies. The Alemany A, Lancet Respir Med, 2022 study (COnV-ert) is extracted elsewhere and reports on longer follow up outcomes up to Day 60. Gharbharan A, Clin Microbiol Infect, 2022 results are included in this trial and only reports results up to Day28. This study was updated on November 18th, 2022 with data extracted from the final publication.

Trial NCT04373460
Publication Sullivan D, N Engl J Med (2022) (published paper)
Dates: 2020-06-03 to 2021-10-01
Funding: Mixed (U.S. Department of Defenses (DOD) Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND), in collaboration with the Defense Health Agency (DHA); Bloomberg Philanthropies; State of Maryland; the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases; NIH National Center for Advancing Translational Sciences; Division of Intramural Research NIAID NIH; Mental Wellness Foundation; Moriah Fund; Octapharma; HealthNetwork Foundation; the Shear Family Foundation.)
Conflict of interest: No

Methods
	RCT Blinding: double blinding
	Location : Multicenter / USA Follow-up duration (days): 28
Inclusion criteria	≥ 18 years of age Competent and capable to provide informed consent Positive molecular test for presence of SARS-CoV-2 in fluid collected by saliva for antigen, oropharyngeal or nasopharyngeal swab Experiencing any symptoms of COVID-19 including but not limited to fever(T> 100.5º F), cough, or other COVID associated symptoms like anosmia ≤ 8 days since the first symptoms of COVID-19 ≤ 8 days since first positive SARS-CoV-2 RNA test Able and willing to comply with protocol requirements listed in the informed consent
Exclusion criteria	Hospitalized or expected to be hospitalized within 24 hours of enrollment Psychiatric or cognitive illness or recreational drug/alcohol use that in the opinion of the principal investigator, would affect subject safety and/or compliance History of prior reactions to transfusion blood products Inability to complete therapy with the study product within 24 hours after enrollment Receiving any treatment drug for COVID-19 within 14 days prior to screening evaluation (monoclonal antibodies, compassionate use or study trial related). Steroid treatment at any time does not affect study eligibility
Interventions
	Treatment Convalescent plasma 250 mL intravenously over 1 hour once-off
	Control Placebo
Participants
	Randomized participants : Convalescent plasma=610 Placebo=615
	Characteristics of participants N= 1225 Mean age : NR 506 males Severity : Mild: n= 1181/ Asymptomatic: n=0
Primary outcome
	In the register 1. Cumulative incidence of hospitalization or death prior to hospitalization [ Time Frame: Up to day 28 ]; 2. Cumulative incidence of treatment-related serious adverse events [ Time Frame: Up to day 28 ]; 3. Cumulative incidence of treatment-related grade 3 or higher adverse events [ Time Frame: Up to day 90 ]
	In the report Covid-19–related hospitalization within 28 days after transfusion, assessed as the cumulative incidence in the convalescent- plasma group as compared with the control-plasma group. Although death before hospitalization was part of the protocol-specified primary outcome, it did not occur in the trial. Hence, the primary outcome is equivalent to Covid-19–related hospitalization.
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 pre-print article, data from contact with authors and the study registry was used in data extraction and risk of bias assessment. Neither protocol nor statistical analysis plane was available. Recruitment to the trial (n = 1225) was terminated due to declining hospitalizations among enrolled participants and thus did not achieve its target sample size (n = 1344).The registry states that at least 175 mL of convalescent plasma would be administered and the pre-print indicates that approximately 250 mL was delivered. One primary outcome in the registry was death prior to hospitalization or hospitalization; as no deaths occurred prior to hospitalization, this outcome is reported as hospitalization. Two other primary safety outcomes are not defined as primary in the article, but are reported. Secondary outcomes reported in the registry are not reported in the pre-print (e.g., change in serum SARS-CoV-2 antibody titers, Time to SARS-CoV-2 Polymerase Chain Reaction (PCR) negativity). The outcomes "hospitalization or death" and "WHO Score 7 and above" were extracted through day 28. Extraction and risk of bias assessments were updated on 28 March 2022 after contact with the study author.