CONvalescent Plasma for Hospitalized Adults With COVID-19 Respiratory Illness (CONCOR-1)
- Conditions
- COVID-19
- Interventions
- Biological: Convalescent plasma
- Registration Number
- NCT04348656
- Lead Sponsor
- Hamilton Health Sciences Corporation
- 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).
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 940
- ≥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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Convalescent plasma Convalescent plasma \~500 mL ABO compatible convalescent apheresis plasma
- Primary Outcome Measures
Name Time Method Number of Participants Who Were Intubated or Died Day 30 Endpoint of the need for intubation or patient death
- Secondary Outcome Measures
Name Time Method Length of Stay in Hospital Day 90 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.
Patient Reported Outcome- Quality-adjusted Life Days Day 30 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.
In-hospital Death Day 90 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.
Time to In-hospital Death Day 90 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.
Death by Day 30 Day 30 Occurrence of patient death at 30 days
Length of Stay in Intensive Care Unit (ICU) Day 30 Number of days spent in the intensive care unit (ICU) over the 30-day period following randomization
Development of Myocarditis Day 30 New diagnosis of myocarditis
Number of Participants With Grade 3, 4, or 5 Serious Adverse Events Day 30 Number of Participants with Grade 3-5 (CTCAE v4.0) serious adverse events reported to Day 30
Patient Reported Outcome Using Change in EQ-5D-5L Score Baseline and Day 30 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.
Cost of Intervention and Hospital Stay Day 30 Cost per patient calculated using cost of the intervention and costs of the hospital stay
Number of Participants With Grade 3 and 4 Serious Adverse Events Day 30 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)
Number of Participants With CCP Transfusion-associated Adverse Events (AE) Day 30 Number of participants experiencing CCP transfusion-associated adverse events (AE), as defined by the International Society of Blood Tranfusion (ISBT ) classification
Time to Intubation or In-hospital Death Day 30 Time in days from randomization to occurrence of intubation or death
Ventilator-free Days by Day 30 Day 30 Number of days off ventilator at 30 days
Need for Renal Replacement Therapy Day 30 Need for new renal replacement therapy
Need for Extracorporeal Membrane Oxygenation (ECMO) Day 30 Requirement for extracorporeal membrane oxygenation (ECMO)
Trial Locations
- Locations (72)
Pasqua Hospital
🇨🇦Regina, Saskatchewan, Canada
Royal University Hospital
🇨🇦Saskatoon, Saskatchewan, Canada
Regina General Hospital
🇨🇦Regina, Saskatchewan, Canada
Brooklyn Hospital
🇺🇸Brooklyn, New York, United States
Lower Manhattan Hospital
🇺🇸New York, New York, United States
Hospital Universitário Antônio Pedro (HUAP)
🇧🇷Niterói, Brazil
Weill Cornell Medical Center
🇺🇸New York, New York, United States
Hemario
🇧🇷Rio De Janeiro, Brazil
Peter Lougheed Center
🇨🇦Calgary, Alberta, Canada
Rockyview General Hospital
🇨🇦Calgary, Alberta, Canada
Fraser Health Authority - Abbotsford Regional Hospital and Cancer Centre
🇨🇦Abbotsford, British Columbia, Canada
Vancouver General Hospital
🇨🇦Vancouver, British Columbia, Canada
Victoria General Hospital
🇨🇦Victoria, British Columbia, 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
Hamilton General Hospital
🇨🇦Hamilton, Ontario, Canada
Juravinski Hospital
🇨🇦Hamilton, Ontario, Canada
St. Joseph's Healthcare
🇨🇦Hamilton, Ontario, Canada
Grand River Hospital
🇨🇦Kitchener, Ontario, Canada
Victoria Hospital
🇨🇦London, Ontario, Canada
Markham Stouffville Hospital
🇨🇦Markham, Ontario, Canada
Trillium Health Partners - Mississauga Hospital
🇨🇦Mississauga, Ontario, Canada
Bluewater Health
🇨🇦Sarnia, Ontario, Canada
Scarborough Health Network, Centenary Hospital
🇨🇦Scarborough, Ontario, Canada
Scarborough Health Network, Birchmount Hospital
🇨🇦Scarborough, Ontario, Canada
Niagara Health System - St. Catherines
🇨🇦St. Catherines, Ontario, Canada
Unity Health St. Michael's Hospital
🇨🇦Toronto, Ontario, Canada
Sinai Health System
🇨🇦Toronto, Ontario, Canada
Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
Unity Health, St. Joseph's Health Care Centre
🇨🇦Toronto, Ontario, Canada
Windsor Regional Hospital - Ouellette Campus
🇨🇦Windsor, Ontario, Canada
L'Hopital Chicoutimi
🇨🇦Chicoutimi, Quebec, Canada
Hotel Dieu Hospital of Lévis
🇨🇦Lévis, Quebec, Canada
Hôpital Maisonneuve-Rosemont
🇨🇦Montréal, Quebec, Canada
McGill University Health Centre
🇨🇦Montréal, Quebec, Canada
Hôpital du Sacré-Coeur de Montreal
🇨🇦Montréal, Quebec, Canada
Centre Hospitalier Universitaire de Sherbrooke (CHUS) - Hôpital Fleurimont
🇨🇦Sherbrooke, Quebec, Canada
Foothills Medical Centre
🇨🇦Calgary, Alberta, Canada
University of Alberta - Royal Alexandra Hospital
🇨🇦Edmonton, Alberta, Canada
Sturgeon Community Hospital
🇨🇦St. Albert, Alberta, Canada
St. Boniface General Hospital
🇨🇦Winnipeg, Manitoba, Canada
Trillium Health Partners - Credit Valley
🇨🇦Mississauga, Ontario, Canada
Lakeridge Health Ajax Pickering
🇨🇦Ajax, Ontario, Canada
St. Mary's Hospital
🇨🇦Kitchener, 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
Toronto Western Hospital
🇨🇦Toronto, Ontario, Canada
Scarborough Health Network, General Hospital
🇨🇦Scarborough, Ontario, Canada
Windsor Regional Hospital - Metropolitan Campus
🇨🇦Windsor, Ontario, Canada
Hôpital Charles-Le Moyne
🇨🇦Longueuil, Quebec, 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
Hôpital de la Cité-de-la-Santé
🇨🇦Laval, Quebec, Canada
Centre hospitalier de l'Université de Montréal
🇨🇦Montréal, Quebec, Canada
Centre hospitalier universitaire Sainte-Justine
🇨🇦Montréal, Quebec, Canada
Centre Hospitalier Universitaire de Sherbrooke (CHUS) - Hôpital Hôtel-Dieu
🇨🇦Sherbrooke, Quebec, Canada
Centre hospitalier régional de St-Jérôme
🇨🇦Saint-Jérôme, Quebec, Canada
Centre hospitalier affilié universitaire régional de Trois-Rivières
🇨🇦Trois-Rivières, Quebec, Canada
Queensway Carleton Hospital
🇨🇦Ottawa, Ontario, Canada
Montréal General Hospital
🇨🇦Montréal, Quebec, Canada
Jewish General Hospital
🇨🇦Montréal, Quebec, Canada
Royal Jubilee Hospital
🇨🇦Victoria, British Columbia, Canada
Dr. Georges-L.-Dumont University Hospital Centre
🇨🇦Moncton, New Brunswick, Canada
University of Alberta Hospital
🇨🇦Edmonton, Alberta, Canada
St. Paul's Hospital
🇨🇦Saskatoon, Saskatchewan, Canada
London Health Sciences Centre - University Hospital
🇨🇦London, Ontario, Canada
Sunnybrook Health Sciences Centre
🇨🇦Toronto, Ontario, Canada