Convalescent Plasma in the Treatment of Covid-19 (CP_COVID-19)

Randomized, Double-Blind, Placebo-Controlled Study of Convalescent Plasma in the Treatment of Covid-19

This study investigates the possible adverse effects and effectiveness of convalescent plasma for patients infected with SARS-CoV-2. Following provision of informed consent, patients will be randomized into three groups: High-titre convalescent plasma, low-titre convalescent plasma or placebo. Primary outcomes of the study will cover safety and either intubation or initiation of systemic corticosteroids. Safety information collected will include serious adverse events judged to be related to administration of convalescent plasma. Microbiological and other laboratory parameters will be followed up.

Study Overview

• Status: Active, not recruiting
• Conditions: Covid19
• Intervention / Treatment: Biological: Convalescent plasma from COVID-19 donors; Biological: Placebo

Detailed Description

SARS-CoV-2 pandemic presents a serious global public health threat urgently requiring both prophylactic and therapeutic interventions. The entry of SARS-CoV-2 into human cells involves a binding between its spike protein's receptor-binding domain (RBD) and angiotensin-converting enzyme 2 (ACE2) receptor on human cells. Convalescent sera of Covid-19 patients have been shown to contain SARS-CoV-2-neutralizing antibodies. Accordingly, recovered patients are presumed to be immune to re-infection. Use of convalescent plasma as treatment warrants research, which is supported by the European Commission. Convalescent plasma (CP) therapy is a classical adaptive immunotherapy. It has been applied to prevention and treatment of various infectious diseases: evidence of success has been accumulated e.g. on treatment of SARS, MERS, and 2009 H1N1, for which satisfactory efficacy and safety have been shown.

The investigators will select as donors for CP therapy patients recovered from Covid-19 with a high neutralizing antibody titre who meet normal blood donor eligibility criteria. The donors will be recruited among participants of ongoing Covid-19 immunity studies (Clin-Covid, Commun-Covid) and/or from Finnish Red Cross Blood Service (FRCBS) blood donors.

CP will be prepared from the blood of eligible donors at the FRCBS according to previous protocols and the European guidelines for fresh frozen plasma. After the screening test results required for product release (HCV, HBV, HIV, ABO, Syphilis) are available, the units will be released. All donors will be screened for type-I-Interferon antibodies and women will be screened for HLA-antibodies. The units will be labelled with convalescence plasma labels including ICCBBA/ISBT compliant product codes. The plasma units will be frozen to -25°C within 6 hours from collection. Prior to freezing 3 ml of CP will be separated and divided in 3 aliquots to be stored, for possible later analysis.

Patients admitted to ward at HUH will be randomized 1:1:1 into three groups which will be given 1) high-titre convalescent plasma (HCP), 2) low-titre convalescent plasma (LCP) or 3) placebo. The plasma preparations and placebo will be given as one 200 mL infusion. ABORh blood group will be determined from patients prior to transfusion according to normal transfusion protocols of the hospital. The study will be double-blinded with saline as placebo given to groups three. The primary outcomes of the study will cover safety and intubation/initiation of systemic corticosteroids. AEs will be reviewed, recorded and reported up to 6 hours after administration of CP or placebo. Thromboembolic and cardiovascular events will be recorded as AEs or SAEs up to 7 days after administration of CP / placebo. SAEs will be reviewed, recorded and reported up to 7 days after administration of CP / placebo. In case of respiratory failures classified as SAEs, the reporting period is only up to 12 hours after administration of CP / placebo.

• Study Type: Interventional
• Enrollment (Anticipated): 390
• Phase: Phase 2

Contacts and Locations

Study Locations

• Finland
  • Uusimaa
    • Helsinki, Uusimaa, Finland, 00270
      • Helsinki University Central Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Acute Covid-19 disease at the time of recruitment laboratory-confirmed by upper respiratory tract PCR
• Patient recently (0-4 days earlier) admitted to hospital due to Covid-19 infection
• Symptom onset 10 days before recruitment (if symptom onset unknown the duration is calculated from positive PCR-test)
• the day should be recorded from the duration of the Covid-19 symptoms/positive test result
• The dose of LMWH thromboprofylaxis should be recorded
• Written informed consent.

Exclusion Criteria:

• Chronic (longer than 14 days) administration of immunosuppressants or other immune-modifying drugs within 6 months before the first dose of IMP; oral corticosteroids in dosages of ≥0.5 mg/kg/d prednisolone or equivalent are excluded ( inhaled or topical steroids allowed)
• Regular (daily), systemic administration of corticosteroids at the time on inclusion (inhaled or topical corticosteroids are allowed)
• Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection.
• Pregnancy or lactation.
• Alcohol or drug abuse.
• Suspected non-compliance.
• Presence of VTE, including pulmonary embolism or other manifestations of thrombosis
• Use of any investigational drug (other than hydroxychloroquine) or vaccine within 30 days prior to first dose of study vaccine or planned use during study period.
• Any clinically significant history of known or suspected anaphylaxis or hypersensitivity reaction as judged by investigator.
• Known immunoglobulin A (IgA) deficiency
• Existing treatment limitations: do-not-resuscitate (DNR) order or withholding treatment in ICU
• Any other criteria which, as judged by investigator, might compromise a patient's well-being or ability to participate in the study or its outcome.
• Active malignant disease
• CP not available for patients blood type
• Patient cannot assign written consent
• No personnel available for CP of placebo transfusion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High-titre CP; 200mL high-titre CP on admittance	Biological: Convalescent plasma from COVID-19 donors; Convalescent plasma from COVID-19 donors
Active Comparator: low-titre CP; 200ml low-titre CP on admittance	Biological: Convalescent plasma from COVID-19 donors; Convalescent plasma from COVID-19 donors
Placebo Comparator: Placebo; 200mL saline as placebo on admittance	Biological: Placebo; 200mL saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety (SAE)	Immediate serious adverse events (SAE) between active and non-active group	SAEs will be reviewed, recorded and reported up to 6 hours after administration of CP or placebo.
Safety (SAE)	Subsequent serious adverse events (SAE) between active and non-active group	SAEs will be recorded and reported up to 7 days after administration of CP or placebo.
Rate of intubation or systemic corticosteroids initiation	Intubation or systemic corticosteroid treatment (e.g. dexamethasone) started for aggravation of Covid-19	21 days post transfusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital stay	Number of days at hospital during the COVID-19 infection hospital period	Through study completion, up to 1 year
Mortality	Proportion of fatal cases during the COVID-19 infection hospital period	Through study completion, up to 1 year
Mortality	Proportion of fatal cases during the COVID-19 infection hospital period	21 days post transfusion
ICU stay	Number of ICU days during the COVID-19 infection hospital period	Within 21 days post transfusion
Ventilator days	Number of ventilator days during the COVID-19 infection hospital period	Within 21 days post transfusion
Severity of respiratory failure	Highest severity of respiratory failure using adapted WHO Clinical Progression Scale	21 days post transfusion
Viral load	Analyses of respiratory tract secretions by SARS-CoV-2 PCR during the COVID-19 infection hospital period	During hospitalizaation, through study completion, up to 1 year
Antibody measurements	Analyses of SARS-CoV-2-specific antibodies in serum and excretions	Through study completion, up to 1 year
Thrombotic complication	Development of a thrombotic complication, including VTE or arterial thrombosis	Through study completion, up to 1 year
The rate of participants presenting with coagulopathy disorders	Development of sepsis-induced coagulopathy or disseminated intravascular coagulation during the COVID-19 infection hospital period	21 days post transfusion
Number of participants with laboratory change	Change in inflammatory (CRP, Ferritin) and coagulopathy (P -APTT, P -AT3, P -Fibr, P -FiDD, P -FVIII., P -Trombai ja P -TT) markers during the COVID-19 infection hospital period	Through study completion, up to 1 year
Adverse effects	Comparison of adverse events between active and non-active group	Through study completion, up to 1 year
Convalescent plasma efficacy	Convalescent plasma (high or low titer) efficacy versus placebo: rate of intubation or initiating systemic corticosteroids during the COVID-19 infection hospital period	21 day post transfusion
Convalescent plasma high vs low titer efficacy	Comparison of efficacy of high titer CP to low titer CP: Rate of intubation or initiating systemic corticosteroids during the COVID-19 infection hospital period	21 day post transfusion
Convalescent plasma efficacy according to donor status	Comparison of efficacy CP obtained from vaccinated donors versus non-vaccinated donors: Rate of intubation or initiating systemic corticosteroids during the COVID-19 infection hospital period	21 day post transfusion

Collaborators and Investigators

• Sponsor: Helsinki University Central Hospital
• Collaborators: Finnish Red Cross Blood Service
• Investigators: Principal Investigator: Anu Kantele, MD,Prof, Helsinki University Central Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2021
• Primary Completion (Actual): January 30, 2022
• Study Completion (Anticipated): January 30, 2023

Study Registration Dates

• First Submitted: January 26, 2021
• First Submitted That Met QC Criteria: January 28, 2021
• First Posted (Actual): January 29, 2021

Study Record Updates

• Last Update Posted (Actual): July 7, 2022
• Last Update Submitted That Met QC Criteria: July 2, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Safety; Covid-19; Convalescent plasma
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: Plasma_Covid-19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No