Convalescent Plasma as Therapy for Covid-19 Severe SARS-CoV-2 Disease (CONCOVID Study) (ConCoVid-19)

Convalescent Plasma Therapy From Recovered Covid-19 Patients as Therapy for Hospitalized Patients With Covid-19

Passive immunization with immunoglobulins is occasionally used as therapy for the treatment of viral infectious diseases. Immunoglobulins are used for the treatment of CMV disease, and is effective as prophylaxis when given soon after exposure to varicella zoster virus, rabies, and hepatitis B virus.

Neutralizing antibodies against MERS, SARS-CoV-1 and SARS-CoV-2 have been shown to be present in patients previously infected with MERS, SARS-CoV-1 and SARS-CoV-2 respectively. During the 2003 SARS outbreak in Hong-Kong,a non-randomized study in hospitalized SARS patients showed that treatment with convalescent plasma (convP) from SARS-recovered donors significantly increased the day 22 discharge rate and decreased mortality. A study in non-human primates showed that rhesus macaques could not be re-infected with SARS-CoV-2 after primary infection.

With no proven effective therapy against COVID, this study will evaluate the safety and efficacy of convalescent plasma from COVID-recovered donors as a treatment for hospitalized patients with symptomatic COVID-19. The study will focus on patients who tested positive for SARS-CoV-2 in the last 96 hours before inclusion

Primary objectives

• Decrease overall mortality in patients within COVID disease

Study design:

This trial is a randomized comparative trial. Patients will be randomized between the infusion of 300mL of convP with standard of care.

Patient population:

Patients with PCR confirmed COVID disease, age >18 years Donors will be included with a known history of COVID who have been asymptomatic for at least 14 days.

Intervention: 300mL of convP Duration of treatment: ConvP will be given as a one-time infusion Duration of follow up: For the primary endpoint: until discharge or death before day 60, whichever comes first. For the secondary endpoints (with separate consent) up to 1 year.

Target number of patients: 426 Target number of donors: 100 Expected duration of accrural: 36 months

Study Overview

• Status: Terminated
• Conditions: COVID-19
• Intervention / Treatment: Biological: Convalescent plasma

Detailed Description

Secondary (exploratory) objectives

• Evaluate the effect of 300ml convP on hospital stay
• Evaluate the change of the 8-point WHO COVID19 disease severity scale on day 15 and 30
• Evaluate the change of the 8-point WHO COVID19 disease severity scale on day 15 in the subgroup of patients with a baseline neutralizing antibody titer (PRNT50) <80
• Evaluate the effect of 300ml convP on mortality in patients admitted to the ICU
• Evaluate the effect of 300ml plasma therapy on hospital days for patients admitted to the ICU within 24 hours after admission
• Evaluate the impact of plasma therapy on the decrease in SARS-CoV2 shedding from airways
• Evaluate the difference in effect of convP on mortality in patients with a duration of symptoms < or > the median duration of symptoms in the study population
• Evaluate the impact of CTL and NK cell immunity on the likelihood of being protected from immune serum transfer
• Safety of convP therapy
• Evaluate the impact of covP on long-term lung function

• Study Type: Interventional
• Enrollment (Actual): 86
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Alkmaar, Netherlands
    • Noordwest Ziekenhuisgroep
  • Amsterdam, Netherlands
    • Onze Lieve Vrouwen Gasthuis
  • Arnhem, Netherlands
    • Rijnstate Ziekenhuis
  • Delft, Netherlands
    • Reinier de Graaf Gasthuis
  • Den Haag, Netherlands
    • Haaglanden Medisch Centrum
  • Eindhoven, Netherlands
    • Catharina Ziekenhuis
  • Enschede, Netherlands
    • Medisch Spectrum Twente
  • Gouda, Netherlands
    • Groene Hart Ziekenhuis
  • Groningen, Netherlands
    • Martini Hospital
  • Haarlem, Netherlands
    • Spaarna Gasthuis
  • Leiderdorp, Netherlands
    • Alrijne Ziekenhuis
  • Nieuwegein, Netherlands
    • Sint Antonius Ziekenhuis
  • Nijmegen, Netherlands
    • Canisius-Wilhelmina Hospital
  • Rotterdam, Netherlands
    • Maasstad Ziekenhuis
  • Terneuzen, Netherlands
    • ZorgSaam Hospital
  • Uden, Netherlands
    • Bernhoven Hospital
  • Venlo, Netherlands
    • VieCuri
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3000 CA
      • Erasmus Medical Center

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:

• Patients with PCR confirmed COVID disease
• Admitted to the hospital
• The most recent PCR positive sample is <96hrs old
• Written informed consent by patient or legal patient representative
• Age at least 18 years

Exclusion Criteria:

• Participation in another intervention trial on the treatment of COVID-19 that falls under the Dutch law human research (WMO) and in which individual patients are randomized to different treatment options
• Known IgA deficiency
• Invasive ventilation for already >96 hours

Donors: Eligibility for plasma donation

Inclusions Criteria:

• A history of COVID infection that was documented by PCR
• Known ABO-Resus(D) blood group
• A screening for irregular antibodies with a titer ≤ 1:32
• Asymptomatic for at least 14 days
• Written informed consent regarding the plasmapheresis procedure
• Tested negative for HIV, HBV, HCV, HEV, HTLV and syfilis

Exclusion Criteria:

• Age <18 years and > 65 years
• Weight <50kg
• Medical history of heart failure
• History of transfusion with red blood cells, platelets or plasma
• History of organ- or tissue transplant
• A cumulative stay in the United Kingdom of ≥ 6 months in the period between 01-01-1980 and 31-12-1996
• A history of i.v. drug use
• Insulin dependent diabetes
• An underlying severe chronic illness (i.e. history of heart failure, cancer or stroke)
• Tested positive for HLA- or HNA-antibodies

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; Standard of care plus 300mL of convalescent plasma from COVID-19 recovered donors	Biological: Convalescent plasma; 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
No Intervention: Standard of care; standard of care (supportive care, oxygen, antibiotics)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall mortality until discharge from the hospital or a maximum of 60 days after admission whichever comes first	the mortality in the 300ml convP group will be compared with the control arm	until hospital discharge or a maximum of 60 days whichever comes first

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Impact of 300ml convP therapy on hospital days	the hospital days in the 300ml convP group will be compared with the control arm	until hospital discharge or a maximum of 60 days whichever comes first
Impact of 300ml convP on weaning from oxygen therapy	A patient will be considered weaned from oxygen therapy when the patient did not receive oxygen for at least 24 hours.	until hospital discharge or a maximum of 60 days whichever comes first
Impact of 300ml convP on overall mortality in patients admitted to the ICU within 24 hours after admission	the overall mortality in hospital days in patients admitted tot the ICU within 24 hours after admission in the 300ml convP group will be compared with the patients admitted tot the ICU within 24 hours after admission in the control arm	until hospital discharge or a maximum of 60 days whichever comes first
Difference in the effect of convP on mortality in patients with a duration of symptoms less or more the median duration of symptoms in the study population	The mortality in patients with a duration of symptoms less than the median duration of symptoms in the study population will be compared with the mortality in patients with a duration of symptoms more than the median duration of symptoms in the study population	hospital discharge or a maximum of 60 days whichever comes first
Impact of 300ml convP therapy on ICU days in patients admitted to the ICU within 24 hours after admission	the ICU days in hospital days in patients admitted to the ICU within 24 hours after admission in the 300ml convP group will be compared with the patients admitted tot the ICU within 24 hours after admission in the control arm	Until hospital discharge, estimated average 4 weeks
Impact of plasma therapy on the decrease in SARS-CoV2 shedding from airways	airway samples will be taken on day 1 - 3 - 5 - 7 - 10 - 14 - and at discharge	until hospital discharge, estimated average 2 weeks
Impact of CTL and NK cell immunity on the likelihood of being protected from immune serum transfer	Blood wil be drawn at day 1, day 7 and day 14	until hospital discharge, extimated average 2 weeks
Safety of convP therapy	Evaluation of Severe Adverse Events and transfusion related adverse events	until hospital discharge or a maximum of 60 days whichever comes first
Change of the 8-point WHO COVID19 disease severity scale on day 15	The WHO COVID19 disease severity scale on day 15 will be compared with the WHO COVID19 disease severity scale on day 1	until day 15
Change of the 8-point WHO COVID19 disease severity scale on day 30	The WHO COVID19 disease severity scale on day 30 will be compared with the WHO COVID19 disease severity scale on day 1 and day 15	until day 30
Change of the 8-point WHO COVID19 disease severity scale on day 15 in the subgroup of patients with a baseline neutralizing antibody titer (PRNT50) <80.	The WHO COVID19 disease severity scale on day 15 will be compared with the WHO COVID19 disease severity scale on day 1 in patients with a baseline neutralizing antibody titer (PRNT50) <80.	until day 15
Impact of plasma therapy on risk of long-term structural lung damage and lung function	Low dose CT and lung function is done 6 weeks after discharge and if abnormal again 3 months after discharge.	up to 12 months after plasma transfusion

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: Prothya Biosolutions
• Investigators: Principal Investigator: Bart Rijnders, MD, PhD, Erasmus Medical Center

Publications and helpful links

General Publications

• Piechotta V, Iannizzi C, Chai KL, Valk SJ, Kimber C, Dorando E, Monsef I, Wood EM, Lamikanra AA, Roberts DJ, McQuilten Z, So-Osman C, Estcourt LJ, Skoetz N. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review. Cochrane Database Syst Rev. 2021 May 20;5(5):CD013600. doi: 10.1002/14651858.CD013600.pub4.
• Chai KL, Valk SJ, Piechotta V, Kimber C, Monsef I, Doree C, Wood EM, Lamikanra AA, Roberts DJ, McQuilten Z, So-Osman C, Estcourt LJ, Skoetz N. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review. Cochrane Database Syst Rev. 2020 Oct 12;10:CD013600. doi: 10.1002/14651858.CD013600.pub3.

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2020
• Primary Completion (Actual): July 1, 2020
• Study Completion (Actual): September 30, 2020

Study Registration Dates

• First Submitted: March 31, 2020
• First Submitted That Met QC Criteria: April 9, 2020
• First Posted (Actual): April 10, 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: NL73489.078.20

Drug and device information, study documents

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