Overview

• 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)

Eligibility

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:
  1. Patients with at least one of the following acquired immune deficiencies
  2. 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