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

COVID-19 Clinical Trial

— CONCOR-1  

Official title:

A Randomized Open-Label Trial of CONvalenscent Plasma for Hospitalized Adults With Acute COVID-19 Respiratory Illness (CONCOR-1)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04348656
• Other study ID #: CONCOR-1
• Status: Terminated
• Phase: Phase 3
• Start date: March 14, 2020
• Est. completion date: June 16, 2021

Study information

• Verified date: March 2022
• Source: McMaster University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Other known NCT identifiers

• NCT04418518

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 940
• Est. completion date: June 16, 2021
• Est. primary completion date: March 5, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

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

Related Conditions & MeSH terms

• COVID-19

Intervention

Biological:
• 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.

Locations

Country	Name	City	State
Brazil	Hospital Universitário Antônio Pedro (HUAP)	Niterói
Brazil	Hemario	Rio De Janeiro
Canada	Fraser Health Authority - Abbotsford Regional Hospital and Cancer Centre	Abbotsford	British Columbia
Canada	Lakeridge Health Ajax Pickering	Ajax	Ontario
Canada	Vitalité Health Network - Acadie-Bathurst	Bathurst	New Brunswick
Canada	Foothills Medical Centre	Calgary	Alberta
Canada	Peter Lougheed Center	Calgary	Alberta
Canada	Rockyview General Hospital	Calgary	Alberta
Canada	Vitalité Health Network - Restigouche	Campbellton	New Brunswick
Canada	L'Hopital Chicoutimi	Chicoutimi	Quebec
Canada	University of Alberta - Royal Alexandra Hospital	Edmonton	Alberta
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Vitalité Health Network- Northwest	Edmundston	New Brunswick
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	Hôpital de la Cité-de-la-Santé	Laval	Quebec
Canada	Hotel Dieu Hospital of Lévis	Lévis	Quebec
Canada	London Health Sciences Centre - University Hospital	London	Ontario
Canada	Victoria Hospital	London	Ontario
Canada	Hôpital Charles-Le Moyne	Longueuil	Quebec
Canada	Markham Stouffville Hospital	Markham	Ontario
Canada	Trillium Health Partners - Credit Valley	Mississauga	Ontario
Canada	Trillium Health Partners - Mississauga Hospital	Mississauga	Ontario
Canada	Dr. Georges-L.-Dumont University Hospital Centre	Moncton	New Brunswick
Canada	Centre hospitalier de l'Université de Montréal	Montréal	Quebec
Canada	Centre hospitalier universitaire Sainte-Justine	Montréal	Quebec
Canada	Hôpital du Sacré-Coeur de Montreal	Montréal	Quebec
Canada	Hôpital Maisonneuve-Rosemont	Montréal	Quebec
Canada	Jewish General Hospital	Montréal	Quebec
Canada	McGill University Health Centre	Montréal	Quebec
Canada	Montréal General Hospital	Montréal	Quebec
Canada	North York General Hospital	North York	Ontario
Canada	Lakeridge Health Oshawa	Oshawa	Ontario
Canada	Ottawa Hospital - Civic Campus	Ottawa	Ontario
Canada	Ottawa Hospital - General Campus	Ottawa	Ontario
Canada	Queensway Carleton Hospital	Ottawa	Ontario
Canada	Centre Hospitalier Universitaire (CHU) de Québec - Université Laval	Quebec City	Quebec
Canada	Institut Universitaire de cardiologie et pneumologie de Québec	Quebec City	Quebec
Canada	Pasqua Hospital	Regina	Saskatchewan
Canada	Regina General Hospital	Regina	Saskatchewan
Canada	Centre hospitalier régional de St-Jérôme	Saint-Jérôme	Quebec
Canada	Bluewater Health	Sarnia	Ontario
Canada	Royal University Hospital	Saskatoon	Saskatchewan
Canada	St. Paul's Hospital	Saskatoon	Saskatchewan
Canada	Scarborough Health Network, Birchmount Hospital	Scarborough	Ontario
Canada	Scarborough Health Network, Centenary Hospital	Scarborough	Ontario
Canada	Scarborough Health Network, General Hospital	Scarborough	Ontario
Canada	Centre Hospitalier Universitaire de Sherbrooke (CHUS) - Hôpital Fleurimont	Sherbrooke	Quebec
Canada	Centre Hospitalier Universitaire de Sherbrooke (CHUS) - Hôpital Hôtel-Dieu	Sherbrooke	Quebec
Canada	Sturgeon Community Hospital	St. Albert	Alberta
Canada	Niagara Health System - St. Catherines	St. Catherines	Ontario
Canada	Sinai Health System	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	Toronto General Hospital	Toronto	Ontario
Canada	Toronto Western Hospital	Toronto	Ontario
Canada	Unity Health St. Michael's Hospital	Toronto	Ontario
Canada	Unity Health, St. Joseph's Health Care Centre	Toronto	Ontario
Canada	Centre hospitalier affilié universitaire régional de Trois-Rivières	Trois-Rivières	Quebec
Canada	St. Paul's Hospital	Vancouver	British Columbia
Canada	Vancouver General Hospital	Vancouver	British Columbia
Canada	Royal Jubilee Hospital	Victoria	British Columbia
Canada	Victoria General Hospital	Victoria	British Columbia
Canada	Windsor Regional Hospital - Metropolitan Campus	Windsor	Ontario
Canada	Windsor Regional Hospital - Ouellette Campus	Windsor	Ontario
Canada	Grace General Hospital	Winnipeg	Manitoba
Canada	Health Sciences Centre Winnipeg	Winnipeg	Manitoba
Canada	St. Boniface General Hospital	Winnipeg	Manitoba
United States	Brooklyn Hospital	Brooklyn	New York
United States	Lower Manhattan Hospital	New York	New York
United States	Weill Cornell Medical Center	New York	New York

Sponsors (7)

Lead Sponsor	Collaborator
Hamilton Health Sciences Corporation	Canadian Blood Services, Héma-Québec, New York Blood Center, Université de Montréal, University of Toronto, Weill Medical College of Cornell University

Countries where clinical trial is conducted

United States,  Brazil,  Canada, 

References & Publications (2)

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.

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. Erratum in: Lancet. 2020 Feb 4;:. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Who Were Intubated or Died	Endpoint of the need for intubation or patient death	Day 30
Secondary	Time to Intubation or In-hospital Death	Time in days from randomization to occurrence of intubation or death	Day 30
Secondary	Ventilator-free Days by Day 30	Number of days off ventilator at 30 days	Day 30
Secondary	Death by Day 30	Occurrence of patient death at 30 days	Day 30
Secondary	Length of Stay in Intensive Care Unit (ICU)	Number of days spent in the intensive care unit (ICU) over the 30-day period following randomization	Day 30
Secondary	Need for Renal Replacement Therapy	Need for new renal replacement therapy	Day 30
Secondary	Need for Extracorporeal Membrane Oxygenation (ECMO)	Requirement for extracorporeal membrane oxygenation (ECMO)	Day 30
Secondary	Development of Myocarditis	New diagnosis of myocarditis	Day 30
Secondary	In-hospital Death	Occurrence of death while in hospital, censored at 90 days. Patients who were still in hospital at Day 30 were followed until Day 90 to capture in-hospital mortality.	Day 90
Secondary	Time to In-hospital Death	Time to in-hospital death at 90 days. Patients who were still in hospital at Day 30 were followed until Day 90 to capture in-hospital mortality.	Day 90
Secondary	Length of Stay in Hospital	Number of days from randomization to death or hospital discharge. Patients still in hospital at Day 30 were followed until Day 90 to capture death or discharge from hospital.	Day 90
Secondary	Number of Participants With Grade 3 and 4 Serious Adverse Events	Number of participants with Grade 3 and 4 (CTCAE v4.0) serious adverse events, and cumulative incidence of Grade 3 and 4 serious adverse events (using MedDRA AE terms)	Day 30
Secondary	Number of Participants With CCP Transfusion-associated Adverse Events (AE)	Number of participants experiencing CCP transfusion-associated adverse events (AE), as defined by the International Society of Blood Tranfusion (ISBT ) classification	Day 30
Secondary	Number of Participants With Grade 3, 4, or 5 Serious Adverse Events	Number of Participants with Grade 3-5 (CTCAE v4.0) serious adverse events reported to Day 30	Day 30
Secondary	Patient Reported Outcome Using Change in EQ-5D-5L Score	Change in score on EQ-5D-5L instrument at Day 30 as compared to baseline. The EQ-5D-5L measures health-related quality of life in five dimensions, namely, mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Patients can report five level impairment, reflecting no, slight, moderate, severe, and extreme problems in each dimension. The range of possible values is -0.148 to 0.949, with a higher score reflecting a better outcome. For the change in score, a positive number indicates that the scores improved from baseline.	Baseline and Day 30
Secondary	Patient Reported Outcome- Quality-adjusted Life Days	Quality-adjusted life days calculated using the EQ-5D-5L score. Quality-adjusted life days is a measure of how well a patient lives for how long. It combines the length of life and quality of life into one value. This is calculated by multiplying the health utility (derived from the EQ-5D-5L score) by the amount of time the patient is alive during the study period. A higher number is better.	Day 30
Secondary	Cost of Intervention and Hospital Stay	Cost per patient calculated using cost of the intervention and costs of the hospital stay	Day 30

External Links

•   Publication of trial results in Nature Medicine