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

• ClinicalTrials.gov Identifier: NCT04730401
• Recruitment Status: Recruiting
• First Posted: January 29, 2021
• Last Update Posted: March 8, 2021
• Sponsor: Helsinki University Central Hospital
• Collaborator: Finnish Red Cross
• Information provided by (Responsible Party): Anu Kantele, Helsinki University Central Hospital

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Covid19	Biological: Convalescent plasma from COVID-19 donors; Biological: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 390 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Double blind, randomized, placebo controlled trial
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Some of the investigators are masked and some are not
• Primary Purpose: Treatment
• Official Title: Randomized, Double-Blind, Placebo-Controlled Study of Convalescent Plasma in the Treatment of Covid-19
• Actual Study Start Date: January 27, 2021
• Estimated Primary Completion Date: August 31, 2021
• Estimated Study Completion Date: December 31, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Safety (SAE) [ Time Frame: SAEs will be reviewed, recorded and reported up to 6 hours after administration of CP or placebo. ]
   Immediate serious adverse events (SAE) between active and non-active group
2. Safety (SAE) [ Time Frame: SAEs will be recorded and reported up to 7 days after administration of CP or placebo. ]
   Subsequent serious adverse events (SAE) between active and non-active group
3. Rate of intubation [ Time Frame: 21 days post transfusion ]
   Intubation (Yes/No)
4. Number of participants initiating systemic corticosteroids [ Time Frame: 21 days post transfuison ]
   Start of systemic corticosteroid for aggravation of COVID-19 infection

Secondary Outcome Measures :

1. Hospital stay [ Time Frame: Through study completion, up to 1 year ]
   Number of days at hospital during the COVID-19 infection hospital period
2. Mortality [ Time Frame: Through study completion, up to 1 year ]
   Proportion of fatal cases during the COVID-19 infection hospital period
3. Mortality [ Time Frame: 21 days post transfusion ]
   Proportion of fatal cases during the COVID-19 infection hospital period
4. ICU stay [ Time Frame: Within 21 days post transfusion ]
   Number of ICU days during the COVID-19 infection hospital period
5. Ventilator days [ Time Frame: Within 21 days post transfusion ]
   Number of ventilator days during the COVID-19 infection hospital period
6. Severity of respiratory failure [ Time Frame: 21 days post transfusion ]
   Highest severity of respiratory failure using adapted WHO Clinical Progression Scale
7. Viral load [ Time Frame: During hospitalizaation, through study completion, up to 1 year ]
   Analyses of respiratory tract secretions by SARS-CoV-2 PCR during the COVID-19 infection hospital period
8. Antibody measurements [ Time Frame: Through study completion, up to 1 year ]
   Analyses of SARS-CoV-2-specific antibodies in serum and excretions
9. Thrombotic complication [ Time Frame: Through study completion, up to 1 year ]
   Development of a thrombotic complication, including VTE or arterial thrombosis
10. The rate of participants presenting with coagulopathy disorders [ Time Frame: 21 days post transfusion ]
    Development of sepsis-induced coagulopathy or disseminated intravascular coagulation during the COVID-19 infection hospital period
11. Number of participants with laboratory change [ Time Frame: Through study completion, up to 1 year ]
    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
12. Adverse effects [ Time Frame: Through study completion, up to 1 year ]
    Comparison of adverse events between active and non-active group
13. Convalescent plasma efficacy [ Time Frame: 21 day post transfusion ]
    Convalescent plasma (high or low titer) efficacy versus placebo: rate of intubation or initiating systemic corticosteroids during the COVID-19 infection hospital period
14. Convalescent plasma high vs low titer efficacy [ Time Frame: 21 day post transfusion ]
    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
15. Convalescent plasma efficacy according to donor status [ Time Frame: 21 day post transfusion ]
    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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Contact: Sari Pakkanen; 0405166165; sari.pakkanen@hus.fi

Contact: Mikael Kajova, MD; +358503476834; mikael.kajova@hus.fi

Locations

Finland

Helsinki University Central Hospital; Recruiting

Helsinki, Uusimaa, Finland, 00270

Contact: Sari Pakkanen sari.pakkanen@hus.fi

Contact: Juuso Paajanen, MD,PhD +358504270071 juuso.paajanen@hus.fi

Sub-Investigator: Juuso Paajanen, MD,PhD

Principal Investigator: Anu Kantele, MD,Prof

Sub-Investigator: Mikael Kajova, MD

Sub-Investigator: Tamim Khawaja, MD

Sub-Investigator: Anu Patjas, MD

Sub-Investigator: Jukka-Pekka Pietilä, MD

Sub-Investigator: Annamari Ranki, MD,Prof

Sub-Investigator: Olli Vapaalahti, MD,Prof

Sub-Investigator: Taina Autti

Sub-Investigator: Jarkko Ihalainen, MD,PhD

Sub-Investigator: Riitta Lassila, MD,Prof

Sub-Investigator: Iris Levonen

Sub-Investigator: Arttu Nousiainen

Sub-Investigator: Andreas Renner, MD

Sub-Investigator: Marianna Riekkinen, MD

Sub-Investigator: Antti Vierikko

Sub-Investigator: Hanna Välimaa

Sponsors and Collaborators

Helsinki University Central Hospital

Finnish Red Cross

Investigators

• Principal Investigator: Anu Kantele, MD,Prof; Helsinki University Central Hospital

More Information

• Responsible Party: Anu Kantele, Professor, Helsinki University Central Hospital
• ClinicalTrials.gov Identifier: NCT04730401
• Other Study ID Numbers: Plasma_Covid-19
• First Posted: January 29, 2021
• Last Update Posted: March 8, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Anu Kantele, Helsinki University Central Hospital:

Covid-19; Convalescent plasma; Safety

Additional relevant MeSH terms:

COVID-19; Respiratory Tract Infections; Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases