Prevention of severe COVID-19 in the elderly by early high-titer plasma (original) (raw)

Abstract

Background Therapies to interrupt progression of early COVID-19 remain elusive. Among them, convalescent plasma in hospitalized patients was unsuccessful, perhaps because antibody should be administered earlier. We advanced plasma infusions to the first 72 hours of symptoms to arrest COVID-19 progression.

Methods A randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against SARS-CoV2 in elderly subjects within 72 hours of mild COVID-19 symptoms. The primary endpoint was severe respiratory disease defined as a respiratory rate ≥30 and/or an O2 sat<93% in room air. The study was interrupted at 76% of its projected sample size, because cases in the region decreased considerably and steady enrollment of study subjects became virtually impossible.

Results 160 patients underwent randomization. In the intention-to-treat analysis (ITT), 13/80(16.2%) patients receiving plasma vs. 25/80(31.2%) receiving placebo experienced severe respiratory disease [RR(95%CI)= 0.52(0.29,0.94); p=0.026)] with an RRR=48%.

A modified ITT analysis, excluding six subjects who experienced the primary endpoint before infusion, showed a larger effect size [RR(95%CI) = 0.40(0.20, 0.81), p=0.007]. High- and low-titer donor analyses, based on a median IgG titer=1:3,200, evidenced a dose-dependent response with an RRR=73.3% for recipients of high-titer plasma (p=0.016) and a number needed to treat (NNT)=4.4. All secondary endpoints exhibited trends towards protection. No solicited adverse events were observed.

Conclusions Early administration of high-titer convalescent plasma against SARS-CoV2 to mildly ill infected seniors reduced COVID-19 progression. This safe, inexpensive, outpatient intervention facilitates access to treatment from industrialized to LMIC, can decompress demands on hospitals, and may contribute to save lives.

Funded by The Bill & Melinda Gates Foundation and The Fundación INFANT Pandemic Fund. Registered in the Dirección de Sangre y Medicina Transfusional del Ministerio de Salud (PAEPCC19), Plataforma PRIISA (1421), and clinicaltrials.gov (NCT04479163).

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work; RL, GPM, DW and FPP are investigators in a phase 3 SARS CoV2 trial from Pfizer; no other relationships or activities that could appear to have influenced the submitted work.

Competing Interest Statement

RL, GPM, DW and FPP are investigators in a phase 3 SARS CoV2 vaccine trial from Pfizer.

Clinical Trial

Registered in the Direccion de Sangre y Medicina Transfusional del MSAL (PAEPCC19; May 29 2020), Plataforma PRIISA (1421; May 17 2020), and clinicaltrials.gov (NCT04479163; July 23 2020 delayed from start date June 4 due to an inadvertent administrative error)

Funding Statement

Funded by The Bill & Melinda Gates Foundation and The Fundacion INFANT Pandemic Fund.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The trial was approved by the institutional review boards of participating institutions and the state of Buenos Aires, and registered in the Direccion de Sangre y Medicina Transfusional del MSAL (PAEPCC19; May 29 2020), Plataforma PRIISA (1421; May 17 2020), and clinicaltrials.gov (NCT04479163; July 23 2020). Full name of Ethics Committee / Institutional Review Board (IRB) for each participating institution: Comite de Etica Central en Investigacion - Ministerio de Salud de la Provincia de Buenos Aires: H.I.G.A. y C. San Juan de Dios, H.Z.G.A. Simplemente Evita, H.Z.G.A. Dr. Carlos Bocalandro and Hospital Central de San Isidro Dr. Melchor Angel Posse (Decision made: approved) Comite de Etica en Investigacion - Clinica y Maternidad Suizo Argentina: Sanatorio de Los Arcos, Centro de Investigacion Clinica OSECAC - Sede Sagrado Corazon, Sanatorio Anchorena, Sanatorio Finochietto (Decision made: approved) Comite de Etica en Investigacion de la Clinica Olivos de SMG: Clinica Olivos (Decision made: approved) Comite Institucional de Revision de Ensayos Clinicos (CIREC) del Hospital Militar Central: Hospital Militar Central Cir My Dr. Cosme Argerich (Decision made: approved) Comite de Etica en Investigacion Clinica (CEIC): Centro Gallego (Decision made: approved) Comite de Etica en Investigacion de CEMIC: Centro de Educacion Medica e Investigaciones Clinicas (CEMIC) (Decision made: approved)

All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

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Data Availability

Individual participant data that underlie the results reported in this article, after de-identification, will be shared. Proposals should be directed to rlibster{at}infant.org.ar.