Convalescent Plasma for Treatment of COVID-19

Convalescent Plasma for Treatment of COVID-19: An Open Randomised Controlled Trial

Convalescent plasma has been shown to be safe and effective for treatment of several diseases. Preliminary data indicate that it is safe for treatment of COVID-19. We found that viremia upon admission identifies patients at 7 fold increased risk of admission to intensive care and 8 fold increased risk of death. CP treatment appeared to result in rapid viral clearance in a small case series. CP appeared to be well tolerated in a phase I study in which patients only received one dose of CP and a phase II study in which CP was given until viremia disappeared (unpublished data).

Randomised controlled studies assessing the efficacy of CP are lacking and thus the efficacy of CP is unknown. Preliminary data indicate that treatment should be given early, prior to development of severe illness. Detection of viremia upon admission identifies a group at high risk of severe disease and death that has the most to benefit from CP. Phase II study data indicates that treatment should be given until SARS-CoV-2 is no longer detected in serum and the donor antibody neutralization titres should be ≥1/640. A randomised controlled trial in which viremic patients are treated with CP with the equivalent of an antibody titre ≥1/640 is thus required to determine if CP can be an effective COVID-19 treatment.

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Biological: SARS-CoV-2 convalescent plasma; Other: Standard of care

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Sweden
  • Stockholm, Sweden, 171 76
    • Department of Geriatrics, Karolinska University Hospital
  • Stockholm, Sweden, 18257
    • Danderyd Hospital
  • Dalarn
    • Falun, Dalarn, Sweden, 79182
      • Department of Infectious Disease, Falu 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:

• Age greater than or equal to 18
• Admitted to a study hospital
• Active COVID-19 defined as symptoms + SARS CoV-2 identified from upper or lower airway samples and blood
• Negative pregnancy test taken before inclusion and use of an acceptable effective method of contraception until treatment discontinuation if the participant is a woman of childbearing potential
• Written informed consent after meeting with a study physician and ability and willingness to complete follow up

Exclusion Criteria:

• No matching plasma donor (Exact matching in the ABO system is required)
• Unavailability of plasma
• Estimated glomerular filtration rate <30 (kidney failure stage III or more)
• Pregnancy (urinary-hcg)
• Breast feeding
• Inability to give informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Convalescent plasma treatment; Participants will receive 200 ml convalescent plasma daily until SARS-CoV-2 is no longer detectable in the blood up to a maximum of 10 CP infusions.; If steroid therapy has not already been initiated, betamethasone 3 mg daily will be given concomitantly with steroid therapy or longer if clinically indicated but for a maximum of 10 days.	Biological: SARS-CoV-2 convalescent plasma; Participants will receive 200 ml convalescent plasma daily until SARS-CoV-2 is no longer detectable in the blood up to a maximum of 10 CP infusions. CP will be given as a slow infusion over 2 hours. CP neutralization titre of ≥ 1/640 or an ELISA reactivity against the Spike protein of SARS-CoV-2 by the Euroimmun commercial assay >9 is desired. New antibody tests are under development and can be used instead if equivalence to neutralization or Euroimmun ELISA is demonstrated.
Active Comparator: Control; Standard of care for COVID-19 patients.	Other: Standard of care; Standard of care as determined by hospital practices for COVID-19 patients.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
COVID-19 related mortality within 28 days	Death of a study participant within 28 days.	Measured 28 days after inclusion into the study.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
COVID-19 related mortality within 60 days	Death of a study participant within 60 days.	Measured 60 days after inclusion into the study.
Requirement of invasive ventilation or Pao2/FiO2 ≤ 70 for ≥ 12 hours in the case of patients not eligible for intensive care	The need for mechanical ventilation and date when this was initiated; For patients not eligible for intensive care: each day when PaO2/FiO2 ratio was less than 70 for ≥ 12 hours. PaO2 and FiO2 will be estimated from SO2% and O2 flow in nasal cannula, face mask or face mask with reservoir based on EPIC II data. A ratio of 70 is approximately equal to 90% SO2 with 8-9 L of Oxygen flow using a face mask with a reservoir.	Until discharged from the hospital, up to 2 months
Adverse events	Possible adverse events will be elicited using a modification and Swedish translation (appendix 6) of Common Terminology Criteria for Adverse Events v5.0 and they will be continuously reported to the sponsor. Adverse events related to convalescent plasma therapy shall be followed to assess reversibility.	The reporting period for AEs starts at inclusion and ends at the final follow-up visit 2 months after inclusion.
Dose of plasma needed to clear viremia	Measured as doses of convalescent plasma administered (1-10 infusions, 200ml).	28 days
Time to clearance of viremia	Blood samples for detection of SARS-CoV-2 in the blood will be taken prior to treatment start, daily during treatment and until two consecutive negative results are obtained.	Until discharged from the hospital, up to 2 months

Collaborators and Investigators

• Sponsor: Joakim Dillner
• Collaborators: Karolinska Institutet; Danderyd Hospital; Falu Hospital

Publications and helpful links

General Publications

• Dillner J, Ursing J. Convalescent plasma for treatment of COVID-19: study protocol for an open randomised controlled trial in Sweden. BMJ Open. 2021 Dec 8;11(12):e048337. doi: 10.1136/bmjopen-2020-048337.

Study record dates

Study Major Dates

• Study Start (Actual): December 3, 2020
• Primary Completion (Actual): January 26, 2022
• Study Completion (Actual): January 26, 2022

Study Registration Dates

• First Submitted: December 1, 2020
• First Submitted That Met QC Criteria: December 1, 2020
• First Posted (Actual): December 2, 2020

Study Record Updates

• Last Update Posted (Actual): February 9, 2022
• Last Update Submitted That Met QC Criteria: January 26, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: SARS-CoV-2 infection; COVID-19 convalescent plasma treatment; Viremia
• 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: CP3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The investigators will be sharing the data, but the management plan is being designed.
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No