CONvalescent Plasma for Hospitalized Adults With COVID-19 Respiratory Illness (CONCOR-1)

NCT ID: NCT04348656

Last Updated: 2022-03-03

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 940 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-03-14
• Study Completion Date: 2021-06-16

Brief Summary

There is currently no treatment available for COVID-19, the acute respiratory illness caused by the novel SAR-CoV-2. Convalescent plasma from patients who have recovered from COVID-19 that contains antibodies to the virus is a potential therapy. On March 25th, 2020, the FDA approved the use of convalescent plasma under the emergency investigational new drug (eIND) category. Randomized trials are needed to determine the efficacy and safety of COVID-19 convalescent plasma for acute COVID-19 infection.

The objective of the CONCOR-1 trial is to determine the efficacy of transfusion of COVID-19 convalescent plasma to adult patients admitted to hospital with COVID-19 infection at decreasing the frequency of in-hospital mortality in patients hospitalized for COVID-19.

It is hypothesized that treating hospitalized COVID-19 patients with convalescent plasma early in their clinical course will reduce the risk of death, and that other outcomes will be improved including risk of intubation, and length of ICU and hospital stay.

This pan-Canadian clinical trial has the potential to improve patient outcomes and reduce the burden on health care resources including reducing the need for ICU beds and ventilators.

Detailed Description

Problem to be addressed: In December 2019, the Wuhan Municipal Health Committee (Wuhan, China) identified an outbreak of viral pneumonia cases of unknown cause. Coronavirus RNA was quickly identified in some of these patients.This novel coronavirus has been designated SARS-CoV-2, and the disease caused by this virus has been designated COVID-19.Outbreak forecasting and mathematical modelling suggest that these numbers will continue to rise [1] in many countries over the coming weeks to months.Global efforts to evaluate novel antivirals and therapeutic strategies to treat COVID-19 have intensified. There is an urgent public health need for rapid development of novel interventions. At present, there is no specific antiviral therapy for coronavirus infections.

Passive immunization:Passive immunization consists in the transfer of antibodies from immunized donor to non-immunized individual in order to transfer transient protection against an infective agent. A physiological example of passive immunization is the transfer of maternal IgG antibodies to the foetus through the placenta to confer humoral protection to newborns in the first years of life. Passive immunization differs from active immunization in which the patient develops their own immune response following contact with the infective agent or vaccine.

Known potential risks and benefits: There is a theoretical risk of antibody-dependent enhancement of infection (ADE) through which virus targeted by non-neutralizing antibodies gain entry into macrophages. Another theoretical risk is that antibody administration to those exposed to SARS-CoV-2 may avoid disease but modify the immune response such that those individuals mount attenuated immune responses, which would leave them vulnerable to subsequent re-infection. Finally, there are risks associated with any transfusion of plasma including transmission of blood transmitted viruses (e.g. HIV, HBV, HCV, etc.), allergic transfusion reactions, including anaphylaxis, febrile non hemolytic transfusion reaction, transfusion related acute lung injury (TRALI), transfusion associated cardiac overload (TACO), and hemolysis should ABO incompatible plasma be administered. Potential benefits of COVID-19 convalescent plasma include improved survival, improvement in symptoms, decreased risk in intubation for mechanical ventilation, decrease risk of intensive care unit (ICU) admission, shortened hospitalization time and suppression of viral load.

Mechanism of action: Transfusion of apheresis frozen plasma (AFP) from COVID-19 convalescent patients allows the transfer of donor neutralizing antibodies directed against SARS-CoV2 antigens to the recipient, thus allowing the generation of passive immunization. Naturally produced human antibody are polyclonal, meaning they are directed against a variety of different viral antigens and epitopes allowing for a general neutralizing effect against the virus rather than focussing on a specific target. Administration of convalescent plasma has been associated with rapid decrease in viral load. It is also possible that passive immunization contributes to improved cell-mediated immunity by favoring the phagocytosis and presentation of viral antigens to host T cells.

Participant recruitment:Only hospitalized COVID-19 patients are eligible so recruitment efforts will be focused on identified consecutive patients admitted to hospital with acute COVID-19 infection. No other external recruitment efforts are planned. At each participating hospital, a process for identifying patients with COVID-19 will be established.

Donor recruitment for Canadian sites: Recovered COVID-19 patients will be identified as potential donors in collaboration with provincial public health services, local health authorities, and individual co-investigators involved in the study. Potential donors may also be recruiting following self-identification on the routine donor questionnaire or through social media. They will be contacted by phone and invited to participate in the program as potential donors. After obtaining verbal consent and reviewing donor selection criteria, eligible participants will be directed to a Héma-Québec collection or Canadian Blood Services apheresis collection site in their area to donate.

Criteria for donors: All donors will need to meet the criteria set forth in the Manual of donor selection criteria in use at Héma-Québec or Canadian Blood ServicesIn addition, donors will require:

• Prior diagnosis of COVID-19 documented by a PCR test at time of infection or by positive anti-SARS-CoV-2 serology following infection
• Male donors, or female donors with no pregnancy history or with negative anti-HLA antibodies
• At least 6 days since last plasma donation
• Provided informed consent
• A complete resolution of symptoms at least 14 days prior to donation

Donor recruitment for United States sites: Recovered COVID-19 patients are being recruited through the New York Blood Center and Weill Cornell Medicine in separate protocols. Potential donors can self-refer via websites but also be referred by physicians or identified via the medical record system. Only donors with laboratory-confirmed history of COVID-19 will be screened. After providing consent and reviewing FDA and NYBC donor eligibility criteria, donors are screened for the presences of SARS-CoV-2 virus in the nasopharynx if screening within 14 days of complete resolution in accordance with current FDA guidance. Criteria for donation are subject to change based on future revision of FDA guidance. Those found to be eligible will be referred to NYBC for donation.

Criteria for donors:

• Provision of informed consent
• Aged 18 to 70 years. Donors are not longer eligible after their 71st birthday.
• Documented molecular diagnosis of SARS-CoV-2 by RT-PCR by nasopharyngeal swab, oropharyngeal swab, or sputum or detection of anti-SARS-CoV-2 IgG in serum.
• Complete resolution of COVID-19 symptoms at least 14 days prior to donation
• Not currently pregnant or pregnant within 6 weeks by self-report
• Male donors, or females with no pregnancy history or with negative anti-HLA antibodies
• Meets blood donor criteria specified by NYBC, which is consistent with FDA regulations.

Donors will be allowed to donate every 7 days. The following information will be collection from donors: ABO group, sex, age, date of onset of symptoms (when available), date of resolution of symptoms (when available), CCP collection date(s).

Randomization procedures: Patients will be randomized in a 2:1 ratio (convalescent plasma vs standard of care). Patients will be randomized using a secure, concealed, computer-generated, web-accessed randomization sequence. Randomization will be stratified by centre and age (<60 and ≥ 60 years). Within each stratum, variable permuted block sized will be used. This approach will ensure that concealment of the treatment sequence is maintained.

Duration of follow-up: Subjects will be followed daily until hospital discharge or death. Patients discharged from hospital before Day 30 will be contacted by telephone on Day 30 ± 3 days to ascertain any AEs, vital status (dead/alive), hospital readmission and need for mechanical ventilation after discharge. Patients discharged from hospital will be contacted at Day 90+/- 7 days to determine vital status. Patients with a prolonged hospital admission will be censored at Day 90. The local study coordinator will collect all study data and record the data in the electronic CRF or paper CRF as per study procedures for each site.

Duration of study: For an individual subject, the study ends 90 days after randomization. The overall study will end when the last randomized subject has completed 90 day follow-up. We estimate that all patient will be enrolled in a period of 6 months, data on the primary endpoint will be available 30 days after last patient enrollment and data on all secondary endpoints will be available after 90-day from last patient enrollment.

Sample size considerations: Assuming a baseline risk of intubation or death of 30% in hospitalized patients with standard of care, a sample size of 1200 (800 in the convalescent plasma arm, and 400 in the standard of care arm) would provide 80% power to detect a relative risk reduction of 25% with convalescent plasma therapy using a 2-tailed test at level α = 0.05 and a 2:1 randomization.

Interim analysis: A single interim analysis is planned when the primary outcome (intubation or mortality at 30 days) is available for 50% of the target sample. An O'Brien-Fleming stopping rule will be used at that time, but treated as a guideline, so there is minimal impact on the threshold for statistical significance for the final significance test of the primary outcome. A DSMB will monitor ongoing results to ensure patient well-being and safety as well as study integrity. The DSMB will be asked to recommend early termination or modification only when there is clear and substantial evidence of a treatment difference.

Final analysis plan: The primary analysis will be based on the intention-to-treat population which will include data from all individuals who have been randomized. Outcomes will be attributed to the arm to which individuals were randomized irrespective of whether they received the planned intervention (e.g. plasma from a convalescent COVID-19 donor).

Conditions

COVID-19

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Convalescent plasma

\~500 mL ABO compatible convalescent apheresis plasma

Group Type: EXPERIMENTAL

Convalescent plasma

Intervention Type: BIOLOGICAL

Patients will receive 500 mL of convalescent plasma (from one single-donor unit of 500 mL or 2 units of 250 mL from 1-2 donations) collected by apheresis from donors who have recovered from COVID-19 and frozen (1 year expiration date from date of collection). The plasma unit will be thawed as per standard blood bank procedures and infused into the patient slowly over 4 hours. When administering 2 units of 250 mL, the 2nd unit will be administered after the first, and no longer than 12 hours later. The patient will be monitored for adverse events as per each site's policies.

Standard of care

Treated as per institutional standard of care.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Convalescent plasma

Patients will receive 500 mL of convalescent plasma (from one single-donor unit of 500 mL or 2 units of 250 mL from 1-2 donations) collected by apheresis from donors who have recovered from COVID-19 and frozen (1 year expiration date from date of collection). The plasma unit will be thawed as per standard blood bank procedures and infused into the patient slowly over 4 hours. When administering 2 units of 250 mL, the 2nd unit will be administered after the first, and no longer than 12 hours later. The patient will be monitored for adverse events as per each site's policies.

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

• ≥16 years old (>18 years of age in the United States)
• Admitted to hospital with confirmed COVID-19 respiratory illness
• Receiving supplemental oxygen
• 500 mL of ABO compatible convalescent plasma is available

Exclusion Criteria

• Onset of respiratory symptoms >12 days prior to randomization
• Intubated or plan in place for intubation
• Plasma is contraindicated (e.g. history of anaphylaxis from transfusion)
• Decision in place for no active treatment

• Minimum Eligible Age: 16 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Canadian Blood Services

OTHER

Sponsor Role: collaborator

Héma-Québec

OTHER

Sponsor Role: collaborator

University of Toronto

OTHER

Sponsor Role: collaborator

Université de Montréal

OTHER

Sponsor Role: collaborator

Weill Medical College of Cornell University

OTHER

Sponsor Role: collaborator

New York Blood Center

OTHER

Sponsor Role: collaborator

Hamilton Health Sciences Corporation

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Donald M Arnold, MD

Role: PRINCIPAL_INVESTIGATOR

McMaster University

Locations

Brooklyn Hospital

Brooklyn, New York, United States

Lower Manhattan Hospital

New York, New York, United States

Weill Cornell Medical Center

New York, New York, United States

Hospital Universitário Antônio Pedro (HUAP)

Niterói, , Brazil

Hemario

Rio de Janeiro, , Brazil

Peter Lougheed Center

Calgary, Alberta, Canada

Foothills Medical Centre

Calgary, Alberta, Canada

Rockyview General Hospital

Calgary, Alberta, Canada

University of Alberta - Royal Alexandra Hospital

Edmonton, Alberta, Canada

University of Alberta Hospital

Edmonton, Alberta, Canada

Sturgeon Community Hospital

St. Albert, Alberta, Canada

Fraser Health Authority - Abbotsford Regional Hospital and Cancer Centre

Abbotsford, British Columbia, Canada

Vancouver General Hospital

Vancouver, British Columbia, Canada

St. Paul's Hospital

Vancouver, British Columbia, Canada

Royal Jubilee Hospital

Victoria, British Columbia, Canada

Victoria General Hospital

Victoria, British Columbia, Canada

St. Boniface General Hospital

Winnipeg, Manitoba, Canada

Health Sciences Centre Winnipeg

Winnipeg, Manitoba, Canada

Grace General Hospital

Winnipeg, Manitoba, Canada

Vitalité Health Network - Acadie-Bathurst

Bathurst, New Brunswick, Canada

Vitalité Health Network - Restigouche

Campbellton, New Brunswick, Canada

Vitalité Health Network- Northwest

Edmundston, New Brunswick, Canada

Dr. Georges-L.-Dumont University Hospital Centre

Moncton, New Brunswick, Canada

Lakeridge Health Ajax Pickering

Ajax, Ontario, Canada

Hamilton General Hospital

Hamilton, Ontario, Canada

Juravinski Hospital

Hamilton, Ontario, Canada

St. Joseph's Healthcare

Hamilton, Ontario, Canada

Grand River Hospital

Kitchener, Ontario, Canada

St. Mary's Hospital

Kitchener, Ontario, Canada

London Health Sciences Centre - University Hospital

London, Ontario, Canada

Victoria Hospital

London, Ontario, Canada

Markham Stouffville Hospital

Markham, Ontario, Canada

Trillium Health Partners - Mississauga Hospital

Mississauga, Ontario, Canada

Trillium Health Partners - Credit Valley

Mississauga, Ontario, Canada

North York General Hospital

North York, Ontario, Canada

Lakeridge Health Oshawa

Oshawa, Ontario, Canada

Ottawa Hospital - General Campus

Ottawa, Ontario, Canada

Ottawa Hospital - Civic Campus

Ottawa, Ontario, Canada

Queensway Carleton Hospital

Ottawa, Ontario, Canada

Niagara Health System - St. Catherines

Saint Catherines, Ontario, Canada

Bluewater Health

Sarnia, Ontario, Canada

Scarborough Health Network, Centenary Hospital

Scarborough Village, Ontario, Canada

Scarborough Health Network, General Hospital

Scarborough Village, Ontario, Canada

Scarborough Health Network, Birchmount Hospital

Scarborough Village, Ontario, Canada

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada

Unity Health St. Michael's Hospital

Toronto, Ontario, Canada

Sinai Health System

Toronto, Ontario, Canada

Toronto General Hospital

Toronto, Ontario, Canada

Toronto Western Hospital

Toronto, Ontario, Canada

Unity Health, St. Joseph's Health Care Centre

Toronto, Ontario, Canada

Windsor Regional Hospital - Metropolitan Campus

Windsor, Ontario, Canada

Windsor Regional Hospital - Ouellette Campus

Windsor, Ontario, Canada

L'Hopital Chicoutimi

Chicoutimi, Quebec, Canada

Hôpital de la Cité-de-la-Santé

Laval, Quebec, Canada

Hotel Dieu Hospital of Lévis

Lévis, Quebec, Canada

Hôpital Charles-Le Moyne

Longueuil, Quebec, Canada

Hôpital Maisonneuve-Rosemont

Montreal, Quebec, Canada

Centre hospitalier de l'Université de Montréal

Montreal, Quebec, Canada

Montréal General Hospital

Montreal, Quebec, Canada

Centre hospitalier universitaire Sainte-Justine

Montreal, Quebec, Canada

Jewish General Hospital

Montreal, Quebec, Canada

McGill University Health Centre

Montreal, Quebec, Canada

Hôpital du Sacré-Coeur de Montreal

Montreal, Quebec, Canada

Centre Hospitalier Universitaire (CHU) de Québec - Université Laval

Québec, Quebec, Canada

Institut Universitaire de cardiologie et pneumologie de Québec

Québec, Quebec, Canada

Centre hospitalier régional de St-Jérôme

Saint-Jérôme, Quebec, Canada

Centre Hospitalier Universitaire de Sherbrooke (CHUS) - Hôpital Hôtel-Dieu

Sherbrooke, Quebec, Canada

Centre Hospitalier Universitaire de Sherbrooke (CHUS) - Hôpital Fleurimont

Sherbrooke, Quebec, Canada

Centre hospitalier affilié universitaire régional de Trois-Rivières

Trois-Rivières, Quebec, Canada

Regina General Hospital

Regina, Saskatchewan, Canada

Pasqua Hospital

Regina, Saskatchewan, Canada

St. Paul's Hospital

Saskatoon, Saskatchewan, Canada

Royal University Hospital

Saskatoon, Saskatchewan, Canada

Countries

United States; Brazil; Canada

References

Wu JT, Leung K, Leung GM. Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study. Lancet. 2020 Feb 29;395(10225):689-697. doi: 10.1016/S0140-6736(20)30260-9. Epub 2020 Jan 31.

Reference Type: BACKGROUND

PMID: 32014114 (View on PubMed)

2. FDA USFDA. Investigational COVID-19 Convalescent Plasma - Emergency INDs [Web]. 2020 [Available from: https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/investigational-covid-19-convalescent-plasma-emergency-inds accessed March 26th 2020.

Reference Type: BACKGROUND

Begin P, Callum J, Jamula E, Cook R, Heddle NM, Tinmouth A, Zeller MP, Beaudoin-Bussieres G, Amorim L, Bazin R, Loftsgard KC, Carl R, Chasse M, Cushing MM, Daneman N, Devine DV, Dumaresq J, Fergusson DA, Gabe C, Glesby MJ, Li N, Liu Y, McGeer A, Robitaille N, Sachais BS, Scales DC, Schwartz L, Shehata N, Turgeon AF, Wood H, Zarychanski R, Finzi A; CONCOR-1 Study Group; Arnold DM. Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial. Nat Med. 2021 Nov;27(11):2012-2024. doi: 10.1038/s41591-021-01488-2. Epub 2021 Sep 9.

Reference Type: DERIVED

PMID: 34504336 (View on PubMed)

Begin P, Callum J, Heddle NM, Cook R, Zeller MP, Tinmouth A, Fergusson DA, Cushing MM, Glesby MJ, Chasse M, Devine DV, Robitalle N, Bazin R, Shehata N, Finzi A, McGeer A, Scales DC, Schwartz L, Turgeon AF, Zarychanski R, Daneman N, Carl R, Amorim L, Gabe C, Ellis M, Sachais BS, Loftsgard KC, Jamula E, Carruthers J, Duncan J, Lucier K, Li N, Liu Y, Armali C, Kron A, Modi D, Auclair MC, Cerro S, Avram M, Arnold DM. Convalescent plasma for adults with acute COVID-19 respiratory illness (CONCOR-1): study protocol for an international, multicentre, randomized, open-label trial. Trials. 2021 May 4;22(1):323. doi: 10.1186/s13063-021-05235-3.

Reference Type: DERIVED

PMID: 33947446 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://www.nature.com/articles/s41591-021-01488-2

Publication of trial results in Nature Medicine

Other Identifiers

CONCOR-1

Identifier Type: -

Identifier Source: org_study_id

NCT04418518

Identifier Type: -

Identifier Source: nct_alias