Early Convalescent Plasma Therapy for High-risk Patients With COVID-19 in Primary Care (the CoV-Early Study) (CoV-Early)

An effective, widely available, and safe treatment that can decrease the duration, severity and fatality of COVID-19 is urgently needed. Also, in the most affected regions the pressure on health care systems including ventilator support capacity can be a limiting factor for survival. Initial studies including from our group indicate that administering convalescent plasma containing high titers of neutralizing antibodies to COVID-19 patients who are already relatively late during the disease course after hospital admission is not effective, which can be explained by high titers of autologous antibodies present in patients. Thus, the antiviral capacity of convalescent plasma is hypothesized to be best positioned early in the disease course and in patients at increased risk for a severe disease course. If effective, any treatment that decreases the need for hospital admission is very valuable but so far, no COVID-19 treatment has been shown to prevent clinical deterioration when given before patients are admitted to the hospital.

Primary objective:

To evaluate the efficacy, feasibility and safety following the administration of convalescent plasma (ConvP) as a therapy for outpatients diagnosed with COVID-19 at increased risk for an unfavourable clinical outcome and within 7 days after symptom onset.

Study design:

This trial is a nationwide multicenter, double blind, randomized controlled trial in the Netherlands. Patients will be randomized between the transfusion of 300mL of convP versus regular fresh frozen plasma (FFP).

Patient population:

Patients with polymerase chain reaction (PCR) confirmed COVID disease with less than 8 days of symptoms, age 70 or older or 50-69 years with at least 1 additional risk factor for severe COVID-19 are eligible.

Intervention:

300mL of convP with a minimum level of neutralizing antibodies.

A total of 690 patients will be included. Expected duration of accrual: 18-24 months Duration of follow up :Day 28 for the primary endpoint

Study Overview

• Status: Terminated
• Conditions: Covid19
• Intervention / Treatment: Biological: ConvP; Biological: FFP

Detailed Description

Secondary (exploratory) objectives

• To evaluate the impact of 300mL convP on mortality
• To evaluate the impact of 300mL convP on hospital admission
• To evaluate the impact of 300mL convP on admission to ICU
• To evaluate the impact of 300mL convP on duration of symptoms
• To evaluate the impact of 300mL convP in relation to the age and clinical frailty of the patient

• Study Type: Interventional
• Enrollment (Actual): 420
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Amersfoort, Netherlands
    • Meander Medisch Centrum
  • Arnhem, Netherlands
    • Rijnstate Ziekenhuis
  • Breda, Netherlands
    • Amphia ziekenhuis
  • Gouda, Netherlands
    • Groene Hart Ziekenhuis
  • Groningen, Netherlands
    • University Medical Center Groningen (UMCG)
  • Haarlem, Netherlands
    • Spaarne Gasthuis
  • Leeuwarden, Netherlands
    • Medisch Centrum Leeuwarden
  • Leiden, Netherlands
    • Leids Universitair Medisch Centrum
  • Nieuwegein, Netherlands
    • Sint Antonius Ziekenhuis
  • Uden, Netherlands
    • Bernhoven Hospital
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3000 CA
      • Erasmus Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• RT-PCR-confirmed COVID-19.
• Symptomatic (e.g but not limited to fatigue, fever, cough, dyspnoea, loss of taste or smell, diarrhea, falls or confusion)
• 70 years or older OR 50-69 years and 1 or more of the risk factors described in the protocol

Exclusion Criteria:

• Life expectancy <28 days in the opinion of the treating physician
• Patient or legal representative is unable to provide written informed consent
• Symptomatic for 8 days or more
• Being admitted to the hospital at the informed consent procedure
• Known previous history of transfusion-related acute lung injury
• Known Immunoglobulin A (IgA) deficiency

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ConvP; 300 mL convalescent plasma with a minimum of neutralizing antibodies	Biological: ConvP; Infusion of plasma retrieved from donors with a history of PCR proven symptomatic COVID. Plasma will be administered according to the Erasmus MC KIS protocol regarding the use of blood products; Other Names: convalescent plasma
Active Comparator: FFP; 300 mL Fresh Frozen plasma	Biological: FFP; Infusion of thawed non-convalescent plasma Plasma will be administered according to the Erasmus Medical Center quality protocol regarding the use of blood products; Other Names: Fresh Frozen Plasma

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Highest disease status	Highest disease status on the 5-point ordinal disease severity scale in the convP group will be compared with the FFP group.	28 days following transfusion of convP or FFP

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of deaths	Percentage of deaths in the convP group compared to the FFP group	28 days following transfusion of convP or FFP
Percentage of hospital admissions	Percentage of hospital admissions in the convP group compared to the FFP group	28 days following transfusion of convP or FFP
Percentage of ICU admissions	Percentage of ICU admissions in the convP group compared to the FFP group	28 days following transfusion of convP or FFP
Disease duration in days of symptoms	Disease duration in days of symptoms in the convP group compared to the FFP group	28 days following transfusion of convP or FFP
Age and clinical frailty score	Age and clinical frailty score stratified analysis of percentage of primary endpoint following transfusion of convP versus FFP.	28 days following transfusion of convP or FFP

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Highest disease status stratified by presence of neutralizing antibodies and by symptom duration at baseline	Analysis of primary endpoint following transfusion of convP versus FFP stratified by the presence of neutralizing antibodies at baseline and by symptom duration at baseline.	28 days following transfusion of convP or FFP
Change in proportion of detectable SARS-Cov-2 RT-PCR results	Change in proportion of detectable SARS-CoV-2 RT-PCR results at day 3, 7, 14 and 28 following transfusion according to the presence of neutralizing antibodies at baseline	Day 3, 7, 14 and 28 following transfusion of convP or FFP

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: Leiden University Medical Center; ZonMw: The Netherlands Organisation for Health Research and Development; Prothya Biosolutions
• Investigators: Principal Investigator: Bart Rijnders, MD, PhD, Erasmus Medical Center

Publications and helpful links

General Publications

• Millat-Martinez P, Gharbharan A, Alemany A, Rokx C, Geurtsvankessel C, Papageourgiou G, van Geloven N, Jordans C, Groeneveld G, Swaneveld F, van der Schoot E, Corbacho-Monne M, Ouchi D, Piccolo Ferreira F, Malchair P, Videla S, Garcia Garcia V, Ruiz-Comellas A, Ramirez-Morros A, Rodriguez Codina J, Amado Simon R, Grifols JR, Blanco J, Blanco I, Ara J, Bassat Q, Clotet B, Baro B, Troxel A, Zwaginga JJ, Mitja O, Rijnders BJA; CoV-Early study group; COnV-ert study group. Prospective individual patient data meta-analysis of two randomized trials on convalescent plasma for COVID-19 outpatients. Nat Commun. 2022 May 11;13(1):2583. doi: 10.1038/s41467-022-29911-3.

Study record dates

Study Major Dates

• Study Start (Actual): October 12, 2020
• Primary Completion (Actual): October 1, 2021
• Study Completion (Actual): March 1, 2022

Study Registration Dates

• First Submitted: October 12, 2020
• First Submitted That Met QC Criteria: October 15, 2020
• First Posted (Actual): October 19, 2020

Study Record Updates

• Last Update Posted (Actual): April 1, 2022
• Last Update Submitted That Met QC Criteria: March 22, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• 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: NL74972.078.20

Drug and device information, study documents

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