A Trial of CONvalescent Plasma for Hospitalized Adults With Acute COVID-19 Respiratory Illness

COVID-19 Clinical Trial

— CONCOR-1  

Official title:

CONCOR-1: A Randomized Open-Label Trial of CONvalescent Plasma for Hospitalized Adults With Acute COVID-19 Respiratory Illness

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04418518
• Other study ID #: 20-04021981
• Status: Recruiting
• Phase: Phase 3
• Start date: June 24, 2020
• Est. completion date: December 2021

Study information

• Verified date: July 2020
• Source: Weill Medical College of Cornell University
• Contact: Celine Arar
• Phone: 212-746-4177
• Email: cea4002[@]med.cornell.edu
• 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.

WCM is a U.S. sub-site to this pan-Canadian clinical trial (NCT04348656) which 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 antibody therapy involves the administration of antibodies to a given agent to a susceptible individual for the purpose of preventing or treating an infectious disease due to that agent. In contrast, active vaccination requires the induction of an immune response that takes time to develop and varies depending on the vaccine recipient. Some immunocompromised patients fail to achieve an adequate immune response. Thus, passive antibody administration is the only means of providing immediate immunity to susceptible persons and immunity of any measurable kind for highly immunocompromised patients. The only antibody type that is currently available for immediate use is that found in human convalescent plasma.The American Food and Drug Agency (FDA) has recently announced clinical trials and a facilitated access to COVID-19 convalescent plasma for use is patients with severe or life-threatening infections [2].

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: Recovered COVID-19 patients will be identified as potential donors in collaboration with 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 New York Blood Center site in their area to donate.

Criteria for donors: All donors between the ages of 18 and 70 will need to meet donor selection criteria set forth by the FDA and NYBC. In 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 At least 14 days since resolution of COVID-19 symptoms 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

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 information / eligibility

• Status: Recruiting
• Enrollment: 1200
• Est. completion date: December 2021
• Est. primary completion date: June 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• =18 years old

• 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 symptoms >12 days prior to randomization

• Intubated or plan for intubation in place

• 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
United States	Brooklyn Methodist Hospital	Brooklyn	New York
United States	Lower Manhattan Hospital	New York	New York
United States	Weill Cornell Medicine	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Weill Medical College of Cornell University	Hamilton Health Sciences Corporation

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Intubation or death in hospital	Endpoint of the need for intubation or patient death in hospital	Day 30
Secondary	Need for Intubation	Endpoint of the need for intubation before 30 days	Day 30
Secondary	Time to intubation	Time in hours to intubation from randomization	Day 30
Secondary	Ventilator-free days	Endpoint of the number of days off ventilator at 30 days	Day 30
Secondary	In-hospital death	In-hospital death censored at 90 days	90 days
Secondary	Time to in-hospital death	Time to in-hospital death at 90 days	Day 90
Secondary	Death at 30 days	Death at 30 days	30 days
Secondary	Length of stay in intensive care unit (ICU)	Date of intensive care unit admission (first date and total number of days)	Day 30
Secondary	Length of stay in hospital	Date of hospital admission (first date and total number of days)	Day 30
Secondary	Need for extracorpeal membrane oxygenation (ECMO)	First date on ECMO and total number of days	Day 30
Secondary	Need for renal replacement therapy	Need for renal replacement therapy	Day 30
Secondary	Development of myocarditis	New myocarditis	Day 30
Secondary	Adverse events and serious adverse events	Transfusion-associated adverse events, Grade 3 and 4 serious adverse events, and cumulative incidence of Grade 3 and 4 adverse events and serious adverse events (using medDRA)	Day 30
Secondary	CCP transfusion-associated adverse events (AE)	CCP transfusion-associated adverse events (AE)	30 days

External Links

•   Investigational COVID-19 Convalescent Plasma - Emergency INDs [Web]. 2020