- Research Question: Does convalescent plasma (CCP) collected from donors who have recovered from COVID-19 and who have a very high titre of anti-SARS-CoV-2 antibodies reduce the risk of hospitalisation (for COVID-19) or death in patients with early symptoms of acute COVID-19 who are vulnerable to this disease compared to standard of care? - Study product: Very high antibody titre COVID-19 convalescent plasma collected more than 15 days after end of symptoms in COVID-19 patients who also had received at least one dose of a SARS-CoV-2 vaccine. - Methodology: Multicentre, randomised, open-label, adaptive superiority trial: COVID-19 very high neutralizing Ab titre convalescent plasma vs standard care in 2 cohorts of vulnerable patients (cohort 1: elderly (≥ 70 years) and younger with comorbidities, cohort 2: immunosuppressed patients). - Study phase: Phase 3 - Intervention: Two units of high antibody titre COVID-19 convalescent plasma to individuals randomised to the intervention group, 2 units from 2 different donors, preferably transfused on the same day. Plasma provided by convalescent vaccinated donors with a minimum antibody titre of 1:640 against delta variant (B1.617.2) or antibody concentration >=4.000 BAU/ml in the QuantiVac anti-SARS-CoV-2 IgG ELISA or >=20.000 U/ml in the Elecsys anti-SARS-CoV-2 CLIA - Randomisation: 1:1 (standard of care + convalescent plasma vs. standard of care) stratified by centre (cohorts 1 and 2)
COVIC-19 is a multicentre international, randomised, open-label adaptive superiority phase
III trial to evaluate the efficacy and safety of COVID-19 convalescent plasma in the
treatment of COVID-19. It is conducted in a harmonized approach in different countries in
Europe.
The study is randomizing adult COVID-19 patients to one of two arms (1:1 ratio): standard of
care or standard of care and very high neutralizing Ab titre convalescent plasma.
Randomization will be stratified by centre and by patient cohort. The control group will
receive 'standard care' therapy. Neither blinding nor placebo will be used to avoid
unnecessary intravenous access.
Standard of care therapy may include anti-SARS-CoV-2 specific medication listed as authorized
in the protocol. Centres should ensure that medications used as standard of care are used
similarly for patients in both treatment arms.
Participating patients will be included in 2 cohorts of vulnerable patients (cohort 1:
elderly (≥ 70 years) and younger with comorbidities (cohort 1: < 70 with comorbidities),
cohort 2: immunosuppressed patients).
All subjects will undergo a series of efficacy and safety assessments, including laboratory
assays. Subjects will be assessed at baseline, and at Days 3, 14, 28, 90 and 180.
Nasopharyngeal swabs (NP) or lower respiratory tract samples will be obtained at D1
(pre-treatment), and at D3, D14 and D28 (and monthly in case of positivity until of
clearance) for cohort 2.
Blood samples will be obtained at D1, D14 and D28 and on the day of hospitalization (if
applicable).
The trial is sponsored by the University Hospital of Besançon in France, the German Red Cross
in Germany and the NHSBT in the United Kingdom.
Biological: Current standard of care and COVID-19 convalescent and vaccinated plasma
ABO compatible convalescent plasma infused intravenously on study day 1 (as soon as possible after randomisation) and the second on day 1 or day 2. Plasma obtained by apheresis from donors who have recovered from COVID-19 infection (at least 14 days after recovery) and have been vaccinated (at least 3 weeks after first dose of vaccine). A combination of both a SARS-CoV-infection and a SARS-CoV-2 vaccination of the donor is required - irrespective of the sequence of infection and vaccination. As far as the availability of CCP units allows, the two plasma units should have been donated by two different convalescents.
Other: Current standard of care
Standard of care therapy may include anti-SARS-CoV-2 specific medication such as, but not limited to:
Casirivimab
Casirivimab / Imdevimab (REGN-COV2 or Ronapreve)
Imdevimab
Sotrovimab (Xevudy)
Tixagevimab / Cilgavimab (Evusheld)
Molnupiravir (MK-4482)
Nirmatrevlir / Ritonavir (Paxlovid)
Remdesivir
Centres should ensure that medications used as standard of care are used similarly for patients in both treatment arms.
Cohort 1: Elderly and high COVID-age population:
Inclusion criteria:
- SARS-CoV-2 RNA detected in a specimen, ≤ 7 days after onset of symptoms
- Symptoms of COVID-19 (so including but not limited to: fever; cough; breathlessness;
chest pain; wheeze; sore throat; haemoptysis; runny nose; fatigue; muscle or joint
pain; confusion; headache; seizures; nausea; vomiting; diarrhoea; abdominal pain; poor
appetite; skin ulcers or rash; ear pain; conjunctivitis; anosmia; bleeding;
lymphadenopathy. The attending clinician will determine if symptoms are consistent
with COVID-19.
- Clinical status not requiring admission to hospital for COVID-19 disease and oxygen
support
- Ability to transfuse (per randomisation) within 7 days after onset of symptoms
- Men or women, 70 years or older OR
- under 70 years with significant comorbidities (arterial hypertension, diabetes,
obesity, asthma or other chronic pulmonary disease, cardiovascular disease,
cerebrovascular disease, chronic kidney disease / dialysis, hemoglobinopathies, liver
disease, chronic neurological disease, rheumatoid arthritis, lupus or psoriasis)
resulting in a 'COVID-age' of 70 years or more according to the ALAMA risk calculator
https://alama.org.uk/covid-19-medical-risk-assessment/
Exclusion Criteria:
- Age < 18 years (France and Germany only)
- Prior or concurrent treatment for COVID-19 (unless listed as authorized)
- History of COVID-19 disease in the last 90 days prior to enrollment
- Prior anti-SARS-CoV-2 immunization
- Contraindication to receiving CCP including previous history of transfusion-related
acute lung injury (TRALI) or moderate or severe allergic reaction to blood components
- Known participant objection to receiving plasma products
- Primary or acquired immune deficiency listed below (see cohort 2)
- Refusal to participate expressed by patient or legally authorised representative
- Pregnancy
Cohort 2: High-risk immunocompromised population
Inclusion criteria:
- SARS-CoV-2 RNA detected in a specimen, ≤ 7 days after onset of symptoms
- Symptoms of COVID-19 (so including but not limited to: fever; cough; breathlessness;
chest pain; wheeze; sore throat; haemoptysis; runny nose; fatigue; muscle or joint
pain; confusion; headache; seizures; nausea; vomiting; diarrhoea; abdominal pain; poor
appetite; skin ulcers or rash; ear pain; conjunctivitis; anosmia; bleeding;
lymphadenopathy. The attending clinician will determine if symptoms are consistent
with COVID-19.
- Clinical status not requiring admission to hospital for COVID-19 disease and oxygen
support
- Ability to transfuse (per randomisation) within 7 days after onset of symptoms
- Male or female with extremely high risk including:
a. Patients with at least one of the following acquired immune deficiencies
i. Lymphoid malignancies treated within the last 12 months ii. Lymphoid malignancies
with persistent hypogammaglobulinaemia (IgG < 5g/L) iii. Myeloid malignancies treated
by chemotherapy within the last 12 months iv. Myeloid malignancies treated by
anti-BCL-2 drugs within the last 12 months v. Myeloid malignancies associated with
prolonged neutropenia (≥ 6 weeks) vi. Solid tumour undergoing treatment with
chemotherapy (until 3 months after completion of the last chemotherapy cycle) vii.
Allogenic hematopoietic stem cell transplantation within the last 12 months or anytime
if on-going treatment for chronic GVHD viii. Organ transplantation ix. Anti-B
(CD20/CD19) MoAb and/or mycophenolate mofetil treatment within the last 12 months x.
Anti-CD19/CD20 CAR-T cell treatment xi. ATG or alemtuzumab treatment within the last 6
months xii. AIDS
OR b. Patients with primary lymphoid immune deficiencies. i. B cell deficiencies (such as
Bruton agammaglobulinemia) ii. T cell deficiencies (such as Wiskott Aldrich disease) iii.
Combined deficiencies (such as Common variable immunodeficiency).
OR c. Patients without detectable seroconversion ≥ 3 weeks after complete vaccination
schedule with an approved vaccine.
Exclusion Criteria:
- Age < 18 years (France and Germany only)
- Prior or concurrent treatment for COVID-19 (dexamethasone, anti-IL-6/IL6R, remdesivir)
except for prophylactic administration of anti-SARS-CoV-2 monoclonal antibodies (pre
or post exposure) and authorized specific treatment
- History of COVID-19 disease in the last 90 days prior to enrollment
- Contraindication to receiving CCP including previous history of transfusion-related
acute lung injury (TRALI) or moderate or severe allergic reaction to blood components
- Known participant objection to receiving plasma products
- Refusal to participate expressed by patient or legally authorised representative
- Pregnancy
CHU Besançon
Besançon, France
Stauferklinikum Schwäbisch Gmünd
Mutlangen, Baden-Wuerttemberg, Germany
Klinikum Stuttgart
Stuttgart, Baden-Wuerttemberg, Germany
Diakonie-Klinikum Stuttgart
Stuttgart, Baden-Wuerttemberg, Germany
Uniklinikum Tübingen
Tübingen, Baden-Wuerttemberg, Germany
Institut für Klinische Transfusionsmedizin (IKT)
Ulm, Baden-Wuerttemberg, Germany
Uniklinikum Ulm
Ulm, Baden-Wuerttemberg, Germany
Universitätsklinikum Brandenburg
Brandenburg an der Havel, Brandenburg, Germany
Universitätsklinikum Frankfurt
Frankfurt, Hessen, Germany
Elblandkliniken Riesa
Riesa, Sachsen, Germany
Charité Medizinische Klinik IV
Berlin, Germany
Klinikum Chemnitz gGmbH
Chemnitz, Germany
Erasmus Medical Center
Rotterdam, Netherlands
NHS Blood and Transplant
Oxford, United Kingdom
Eric Toussirot, MD, PhD
+333 81 21 83 96
etoussirot@chu-besancon.fr