Clinical trial NCT04342182: Convalescent Plasma as Therapy for Covid-19 Severe SARS-CoV-2 Disease (CONCOVID Study)
Official title: Convalescent Plasma Therapy From Recovered Covid-19 Patients as Therapy for Hospitalized Patients With Covid-19
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: COVID-19
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
Collaborators: name: Prothya Biosolutions
First posted: 2020-04-10
Enrollment: 86
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This trial is a randomized comparative trial. Patients will be randomized between the infusion of 300mL of convP versus the standard of care.
Primary purpose: TREATMENT

Brief summary: 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

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

Eligibility criteria: 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

Primary outcomes:
measure: Overall mortality until discharge from the hospital or a maximum of 60 days after admission whichever comes first
timeFrame: until hospital discharge or a maximum of 60 days whichever comes first
Secondary outcomes:
measure: Impact of 300ml convP therapy on hospital days
timeFrame: until hospital discharge or a maximum of 60 days whichever comes first
measure: Impact of 300ml convP on weaning from oxygen therapy
timeFrame: until hospital discharge or a maximum of 60 days whichever comes first
measure: Impact of 300ml convP on overall mortality in patients admitted to the ICU within 24 hours after admission
timeFrame: until hospital discharge or a maximum of 60 days whichever comes first
measure: 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
timeFrame: hospital discharge or a maximum of 60 days whichever comes first
measure: Impact of 300ml convP therapy on ICU days in patients admitted to the ICU within 24 hours after admission
timeFrame: Until hospital discharge, estimated average 4 weeks
measure: Impact of plasma therapy on the decrease in SARS-CoV2 shedding from airways
timeFrame: until hospital discharge, estimated average 2 weeks
measure: Impact of CTL and NK cell immunity on the likelihood of being protected from immune serum transfer
timeFrame: until hospital discharge, extimated average 2 weeks
measure: Safety of convP therapy
timeFrame: until hospital discharge or a maximum of 60 days whichever comes first
measure: Change of the 8-point WHO COVID19 disease severity scale on day 15
timeFrame: until day 15
measure: Change of the 8-point WHO COVID19 disease severity scale on day 30
timeFrame: until day 30
measure: 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.
timeFrame: until day 15
measure: Impact of plasma therapy on risk of long-term structural lung damage and lung function
timeFrame: up to 12 months after plasma transfusion
Other outcomes:
Locations:
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
state: Zuid-Holland
city: Alkmaar
country: Netherlands
facility: NoordWest Ziekenhuisgroep
city: Amsterdam
country: Netherlands
facility: Onze Lieve Vrouwen Gasthuis
city: Arnhem
country: Netherlands
facility: Rijnstate Ziekenhuis
city: Delft
country: Netherlands
facility: Reinier de Graaf Gasthuis
city: Den Haag
country: Netherlands
facility: Haaglanden Medisch Centrum
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Gouda
country: Netherlands
facility: Groene Hart Ziekenhuis
city: Groningen
country: Netherlands
facility: Martini Hospital
city: Haarlem
country: Netherlands
facility: Spaarna Gasthuis
city: Leiderdorp
country: Netherlands
facility: Alrijne Ziekenhuis
city: Nieuwegein
country: Netherlands
facility: Sint Antonius Ziekenhuis
city: Nijmegen
country: Netherlands
facility: Canisius-Wilhelmina Hospital
city: Rotterdam
country: Netherlands
facility: Maasstad Ziekenhuis
city: Terneuzen
country: Netherlands
facility: ZorgSaam Hospital
city: Uden
country: Netherlands
facility: Bernhoven Hospital
city: Venlo
country: Netherlands
facility: VieCuri
Study officials:
affiliation: Erasmus Medical Center
name: Bart Rijnders, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.