Clinical trial NCT04348656: CONvalescent Plasma for Hospitalized Adults With COVID-19 Respiratory Illness (CONCOR-1)
Official title: A Randomized Open-Label Trial of CONvalenscent Plasma for Hospitalized Adults With Acute COVID-19 Respiratory Illness (CONCOR-1)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: COVID-19
Keywords: Convalescent plasma
Transfusion
SARS-CoV-2
Passive immunization
Lead sponsor: McMaster University
Sponsor class: OTHER
Collaborators: name: Canadian Blood Services
name: Héma-Québec
name: University of Toronto
name: Université de Montréal
name: Weill Medical College of Cornell University
name: New York Blood Center
First posted: 2020-04-16
Enrollment: 940
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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

Primary outcomes:
measure: Number of Participants Who Were Intubated or Died
timeFrame: Day 30
Secondary outcomes:
measure: Time to Intubation or In-hospital Death
timeFrame: Day 30
measure: Ventilator-free Days by Day 30
timeFrame: Day 30
measure: Death by Day 30
timeFrame: Day 30
measure: Length of Stay in Intensive Care Unit (ICU)
timeFrame: Day 30
measure: Need for Renal Replacement Therapy
timeFrame: Day 30
measure: Need for Extracorporeal Membrane Oxygenation (ECMO)
timeFrame: Day 30
measure: Development of Myocarditis
timeFrame: Day 30
measure: In-hospital Death
timeFrame: Day 90
measure: Time to In-hospital Death
timeFrame: Day 90
measure: Length of Stay in Hospital
timeFrame: Day 90
measure: Number of Participants With Grade 3 and 4 Serious Adverse Events
timeFrame: Day 30
measure: Number of Participants With CCP Transfusion-associated Adverse Events (AE)
timeFrame: Day 30
measure: Number of Participants With Grade 3, 4, or 5 Serious Adverse Events
timeFrame: Day 30
measure: Patient Reported Outcome Using Change in EQ-5D-5L Score
timeFrame: Baseline and Day 30
measure: Patient Reported Outcome- Quality-adjusted Life Days
timeFrame: Day 30
measure: Cost of Intervention and Hospital Stay
timeFrame: Day 30
Other outcomes:
Locations:
city: Brooklyn
country: United States
facility: Brooklyn Hospital
state: New York
city: New York
country: United States
facility: Lower Manhattan Hospital
state: New York
city: New York
country: United States
facility: Weill Cornell Medical Center
state: New York
city: Niterói
country: Brazil
facility: Hospital Universitário Antônio Pedro (HUAP)
city: Rio De Janeiro
country: Brazil
facility: Hemario
city: Calgary
country: Canada
facility: Peter Lougheed Center
state: Alberta
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Calgary
country: Canada
facility: Rockyview General Hospital
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta - Royal Alexandra Hospital
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: St. Albert
country: Canada
facility: Sturgeon Community Hospital
state: Alberta
city: Abbotsford
country: Canada
facility: Fraser Health Authority - Abbotsford Regional Hospital and Cancer Centre
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Victoria
country: Canada
facility: Royal Jubilee Hospital
state: British Columbia
city: Victoria
country: Canada
facility: Victoria General Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: St. Boniface General Hospital
state: Manitoba
city: Winnipeg
country: Canada
facility: Health Sciences Centre Winnipeg
state: Manitoba
city: Winnipeg
country: Canada
facility: Grace General Hospital
state: Manitoba
city: Bathurst
country: Canada
facility: Vitalité Health Network - Acadie-Bathurst
state: New Brunswick
city: Campbellton
country: Canada
facility: Vitalité Health Network - Restigouche
state: New Brunswick
city: Edmundston
country: Canada
facility: Vitalité Health Network- Northwest
state: New Brunswick
city: Moncton
country: Canada
facility: Dr. Georges-L.-Dumont University Hospital Centre
state: New Brunswick
city: Ajax
country: Canada
facility: Lakeridge Health Ajax Pickering
state: Ontario
city: Hamilton
country: Canada
facility: Hamilton General Hospital
state: Ontario
city: Hamilton
country: Canada
facility: Juravinski Hospital
state: Ontario
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare
state: Ontario
city: Kitchener
country: Canada
facility: Grand River Hospital
state: Ontario
city: Kitchener
country: Canada
facility: St. Mary's Hospital
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre - University Hospital
state: Ontario
city: London
country: Canada
facility: Victoria Hospital
state: Ontario
city: Markham
country: Canada
facility: Markham Stouffville Hospital
state: Ontario
city: Mississauga
country: Canada
facility: Trillium Health Partners - Mississauga Hospital
state: Ontario
city: Mississauga
country: Canada
facility: Trillium Health Partners - Credit Valley
state: Ontario
city: North York
country: Canada
facility: North York General Hospital
state: Ontario
city: Oshawa
country: Canada
facility: Lakeridge Health Oshawa
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital - General Campus
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital - Civic Campus
state: Ontario
city: Ottawa
country: Canada
facility: Queensway Carleton Hospital
state: Ontario
city: Sarnia
country: Canada
facility: Bluewater Health
state: Ontario
city: Scarborough
country: Canada
facility: Scarborough Health Network, Centenary Hospital
state: Ontario
city: Scarborough
country: Canada
facility: Scarborough Health Network, General Hospital
state: Ontario
city: Scarborough
country: Canada
facility: Scarborough Health Network, Birchmount Hospital
state: Ontario
city: St. Catherines
country: Canada
facility: Niagara Health System - St. Catherines
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Unity Health St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sinai Health System
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto Western Hospital
state: Ontario
city: Toronto
country: Canada
facility: Unity Health, St. Joseph's Health Care Centre
state: Ontario
city: Windsor
country: Canada
facility: Windsor Regional Hospital - Metropolitan Campus
state: Ontario
city: Windsor
country: Canada
facility: Windsor Regional Hospital - Ouellette Campus
state: Ontario
city: Chicoutimi
country: Canada
facility: L'Hopital Chicoutimi
state: Quebec
city: Laval
country: Canada
facility: Hôpital de la Cité-de-la-Santé
state: Quebec
city: Longueuil
country: Canada
facility: Hôpital Charles-Le Moyne
state: Quebec
city: Lévis
country: Canada
facility: Hotel Dieu Hospital of Lévis
state: Quebec
city: Montréal
country: Canada
facility: Hôpital Maisonneuve-Rosemont
state: Quebec
city: Montréal
country: Canada
facility: Centre hospitalier de l'Université de Montréal
state: Quebec
city: Montréal
country: Canada
facility: Montréal General Hospital
state: Quebec
city: Montréal
country: Canada
facility: Centre hospitalier universitaire Sainte-Justine
state: Quebec
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Montréal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Montréal
country: Canada
facility: Hôpital du Sacré-Coeur de Montreal
state: Quebec
city: Quebec City
country: Canada
facility: Centre Hospitalier Universitaire (CHU) de Québec - Université Laval
state: Quebec
city: Quebec City
country: Canada
facility: Institut Universitaire de cardiologie et pneumologie de Québec
state: Quebec
city: Saint-Jérôme
country: Canada
facility: Centre hospitalier régional de St-Jérôme
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre Hospitalier Universitaire de Sherbrooke (CHUS) - Hôpital Hôtel-Dieu
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre Hospitalier Universitaire de Sherbrooke (CHUS) - Hôpital Fleurimont
state: Quebec
city: Trois-Rivières
country: Canada
facility: Centre hospitalier affilié universitaire régional de Trois-Rivières
state: Quebec
city: Regina
country: Canada
facility: Regina General Hospital
state: Saskatchewan
city: Regina
country: Canada
facility: Pasqua Hospital
state: Saskatchewan
city: Saskatoon
country: Canada
facility: St. Paul's Hospital
state: Saskatchewan
city: Saskatoon
country: Canada
facility: Royal University Hospital
state: Saskatchewan
Study officials:
affiliation: McMaster University
name: Donald M Arnold, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.