Plasma Therapy of COVID-19 in Severely Ill Patients

A Phase 2, Multi-Center, Randomized Clinical Trial to Evaluate the Efficacy and Safety of Human Anti-SARS-CoV-2 Convalescent Plasma in Severely Ill Adults With COVID-19

This randomized blinded multi-center phase 2 trial will assess the efficacy and safety of anti-SARS-CoV-2 convalescent plasma among adults with severe COVID-19. Adults ≥18 years of age may participate. A total of 219 eligible subjects will be randomized in a 2:1 ratio to receive either high-titer anti-SARS-CoV-2 plasma or non-convalescent fresh frozen plasma (control plasma).

Study Overview

• Status: Completed
• Conditions: SARS-CoV-2 Infection
• Intervention / Treatment: Biological: Convalescent Plasma (anti-SARS-CoV-2 plasma); Biological: Non-convalescent Plasma (control plasma)

Detailed Description

There are few effective therapies for coronavirus disease 2019 (COVID-19) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Exposure to viruses results in an adaptive immune response that commonly include antibodies with neutralization activity. Plasma from subjects who have recovered from viral infections has been used to both prevent or treat disease. Notable examples of the successful use of convalescent plasma (CP) include influenza, measles, Argentine hemorrhagic fever, Middle East respiratory syndrome (MERS), Ebola and severe acute respiratory syndrome (SARS-CoV). Small clinical trials and observational studies of CP therapy in patients with COVID-19 have suggested a possible clinical benefit.

• Study Type: Interventional
• Enrollment (Actual): 223
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Rio De Janeiro, Brazil
    • Hospital Federal dos Servidores do Estado
  • Rio De Janeiro, Brazil
    • Hospital Geral de Nova Iguaçu
  • Rio De Janeiro, Brazil
    • Instituto Nacional de Infectologia Evandro Chagas
• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center/NYP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Willing and able to provide written informed consent prior to performing study procedures or have a legally authorized representative available to do so.
• Age ≥18 years
• Evidence of SARS-CoV-2 infection by PCR test of naso-/oro-pharyngeal swab or tracheal aspirate sample within 14 days of randomization
• Peripheral capillary oxygen saturation (SpO2) ≤ 94% on room air or requiring supplemental oxygen, non-invasive or invasive mechanical ventilation at screening
• Evidence of infiltrates on chest radiography
• Females of childbearing age and males, must be willing to practice an effective contraceptive method or remain abstinent during the study period.

Exclusion Criteria:

• Participation in another clinical trial of anti-viral agent(s) for COVID-19
• Receipt of any anti-viral agent(s) with possible activity against SARS-CoV-2 <24 hours prior to study drug administration [1]
• Mechanically ventilated (including veno-venous (VV)-ECMO) ≥ 5 days
• Severe multi-organ failure
• History of prior reactions to transfusion blood products meeting definitive case definition criteria, at least severe severity, and probable or definite imputability per National Healthcare Safety Network (NHSN)/Centers for Disease Control and Prevention (CDC) criteria
• Known Immunoglobulin A (IgA) deficiency

• Females who are pregnant

  1. Use of remdesivir as treatment for COVID-19 is permitted.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Convalescent Plasma (anti-SARS-CoV-2 plasma); Convalescent plasma (1 unit; ~200-250 mL) collected from a volunteer who recovered from COVID-19 disease	Biological: Convalescent Plasma (anti-SARS-CoV-2 plasma); Convalescent Plasma that contains antibody titers against SARS-CoV-2
Active Comparator: Non-convalescent Plasma (control plasma); Non-convalescent plasma (1 unit; ~200-250 mL) of standard plasma collected prior to December 2019	Biological: Non-convalescent Plasma (control plasma); Non-convalescent plasma (does not contain antibody titers against SARS-CoV-2)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Day 28 Severity Outcomes Using a 7-point Ordinal Scale of Clinical Status	Compare the day 28 severity outcome amongst the anti-SARS-CoV-2 convalescent plasma and non-convalescent plasma groups using a 7-point ordinal scale of clinical status. Seven-point ordinal scale for clinical assessment ranges from 1 and 2: Not hospitalized 3: Hospitalized, not requiring supplemental oxygen 4: Hospitalized, requiring supplemental oxygen 5: Hospitalized, requiring high-flow oxygen therapy or noninvasive mechanical ventilation 6: Hospitalized, requiring IMV, ECMO, or both 7: Dead Higher number means worse outcome	Up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of SARS-CoV-2 PCR Positivity	Compare the proportion and duration of SARS-CoV-2 PCR positivity (via RT-PCR) amongst the anti-SARS-CoV-2 convalescent plasma and non-convalescent plasma groups at days 0, 7, and 14.	Up to 14 days
Levels of SARS-CoV-2 RNA	Compare levels of SARS-CoV-2 RNA amongst the anti-SARS-CoV-2 convalescent plasma and non-convalescent plasma groups at days 0, 7, and 14.	Up to 14 days
Duration of Need for Supplemental Oxygen	Compare duration of need for supplemental oxygen and/or mechanical ventilation amongst the anti-SARS-CoV-2 convalescent plasma and non-convalescent plasma groups.	Up to 28 days
Duration of Hospitalization	Compare duration of hospitalization amongst the anti-SARS-CoV-2 convalescent plasma and non-convalescent plasma groups.	Up to 28 days
28-day Mortality	Compare up to 28-day mortality amongst the anti-SARS-CoV-2 convalescent plasma and non-convalescent plasma groups.	Up to 28 days
Time-to-clinical Improvement In-hospital	Compare time-to-clinical improvement in-hospital amongst the anti-SARS-CoV-2 convalescent plasma and non-convalescent plasma groups, defined as the time to either an improvement of clinical status or alive discharge from the hospital, whichever comes first.	Up to 28 days
Host Genetic Differences at Day 0	To assess for host genetic differences at Day 0 amongst the anti-SARS-CoV-2 convalescent plasma and non-convalescent plasma groups.	Day 0
Host Transcriptomic Differences at Days 0,7,14	To assess for host transcriptomic differences at Day 0,7,14 amongst the anti-SARS-CoV-2 convalescent plasma and non-convalescent plasma groups.	Up to 14 days

Collaborators and Investigators

• Sponsor: Max O'Donnell
• Collaborators: New York Blood Center; Amazon.com, Inc.
• Investigators: Principal Investigator: Max O'Donnell, MD, Columbia University

Publications and helpful links

General Publications

• Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, Wang F, Li D, Yang M, Xing L, Wei J, Xiao H, Yang Y, Qu J, Qing L, Chen L, Xu Z, Peng L, Li Y, Zheng H, Chen F, Huang K, Jiang Y, Liu D, Zhang Z, Liu Y, Liu L. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020 Apr 28;323(16):1582-1589. doi: 10.1001/jama.2020.4783.
• Cheng Y, Wong R, Soo YO, Wong WS, Lee CK, Ng MH, Chan P, Wong KC, Leung CB, Cheng G. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005 Jan;24(1):44-6. doi: 10.1007/s10096-004-1271-9.
• Piechotta V, Iannizzi C, Chai KL, Valk SJ, Kimber C, Dorando E, Monsef I, Wood EM, Lamikanra AA, Roberts DJ, McQuilten Z, So-Osman C, Estcourt LJ, Skoetz N. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review. Cochrane Database Syst Rev. 2021 May 20;5(5):CD013600. doi: 10.1002/14651858.CD013600.pub4.
• Casadevall A, Scharff MD. Serum therapy revisited: animal models of infection and development of passive antibody therapy. Antimicrob Agents Chemother. 1994 Aug;38(8):1695-702. doi: 10.1128/AAC.38.8.1695. No abstract available.
• Arabi YM, Hajeer AH, Luke T, Raviprakash K, Balkhy H, Johani S, Al-Dawood A, Al-Qahtani S, Al-Omari A, Al-Hameed F, Hayden FG, Fowler R, Bouchama A, Shindo N, Al-Khairy K, Carson G, Taha Y, Sadat M, Alahmadi M. Feasibility of Using Convalescent Plasma Immunotherapy for MERS-CoV Infection, Saudi Arabia. Emerg Infect Dis. 2016 Sep;22(9):1554-61. doi: 10.3201/eid2209.151164.
• Austin PC, Fine JP. Practical recommendations for reporting Fine-Gray model analyses for competing risk data. Stat Med. 2017 Nov 30;36(27):4391-4400. doi: 10.1002/sim.7501. Epub 2017 Sep 15.
• Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, Kong Y, Ren L, Wei Q, Mei H, Hu C, Tao C, Yang R, Wang J, Yu Y, Guo Y, Wu X, Xu Z, Zeng L, Xiong N, Chen L, Wang J, Man N, Liu Y, Xu H, Deng E, Zhang X, Li C, Wang C, Su S, Zhang L, Wang J, Wu Y, Liu Z. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA. 2020 Aug 4;324(5):460-470. doi: 10.1001/jama.2020.10044. Erratum In: JAMA. 2020 Aug 4;324(5):519. doi: 10.1001/jama.2020.13216.
• Liu STH, Lin HM, Baine I, Wajnberg A, Gumprecht JP, Rahman F, Rodriguez D, Tandon P, Bassily-Marcus A, Bander J, Sanky C, Dupper A, Zheng A, Nguyen FT, Amanat F, Stadlbauer D, Altman DR, Chen BK, Krammer F, Mendu DR, Firpo-Betancourt A, Levin MA, Bagiella E, Casadevall A, Cordon-Cardo C, Jhang JS, Arinsburg SA, Reich DL, Aberg JA, Bouvier NM. Convalescent plasma treatment of severe COVID-19: a propensity score-matched control study. Nat Med. 2020 Nov;26(11):1708-1713. doi: 10.1038/s41591-020-1088-9. Epub 2020 Sep 15.
• O'Donnell MR, Grinsztejn B, Cummings MJ, Justman JE, Lamb MR, Eckhardt CM, Philip NM, Cheung YK, Gupta V, Joao E, Pilotto JH, Diniz MP, Cardoso SW, Abrams D, Rajagopalan KN, Borden SE, Wolf A, Sidi LC, Vizzoni A, Veloso VG, Bitan ZC, Scotto DE, Meyer BJ, Jacobson SD, Kantor A, Mishra N, Chauhan LV, Stone EF, Dei Zotti F, La Carpia F, Hudson KE, Ferrara SA, Schwartz J, Stotler BA, Lin WW, Wontakal SN, Shaz B, Briese T, Hod EA, Spitalnik SL, Eisenberger A, Lipkin WI. A randomized double-blind controlled trial of convalescent plasma in adults with severe COVID-19. J Clin Invest. 2021 Jul 1;131(13):e150646. doi: 10.1172/JCI150646.
• Eckhardt CM, Cummings MJ, Rajagopalan KN, Borden S, Bitan ZC, Wolf A, Kantor A, Briese T, Meyer BJ, Jacobson SD, Scotto D, Mishra N, Philip NM, Stotler BA, Schwartz J, Shaz B, Spitalnik SL, Eisenberger A, Hod EA, Justman J, Cheung K, Lipkin WI, O'Donnell MR. Evaluating the efficacy and safety of human anti-SARS-CoV-2 convalescent plasma in severely ill adults with COVID-19: A structured summary of a study protocol for a randomized controlled trial. Trials. 2020 Jun 8;21(1):499. doi: 10.1186/s13063-020-04422-y. Erratum In: Trials. 2020 Jun 16;21(1):536. doi: 10.1186/s13063-020-04504-x. Trials. 2020 Nov 17;21(1):927. doi: 10.1186/s13063-020-04877-z.

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2020
• Primary Completion (Actual): December 30, 2020
• Study Completion (Actual): December 30, 2020

Study Registration Dates

• First Submitted: April 21, 2020
• First Submitted That Met QC Criteria: April 21, 2020
• First Posted (Actual): April 24, 2020

Study Record Updates

• Last Update Posted (Actual): September 19, 2024
• Last Update Submitted That Met QC Criteria: August 22, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Coronavirus; COVID-19; COVID; Convalescent plasma
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: AAAS9924

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The data-sharing plans for this study will be made available at a later date.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No