Early High-Titre Convalescent Plasma in Clinically Vulnerable Individuals With Mild COVID-19

Study Overview
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Brief Summary
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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)

Detailed Description
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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.

Official Title
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A Randomised Open-Label Trial of Early, Very High-Titre Convalescent Plasma Therapy in Clinically Vulnerable Individuals With Mild COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Biological: Current standard of care and COVID-19 convalescent and vaccinated plasma
* Other: Current standard of care


Participation Criteria
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Eligibility Criteria
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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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Current standard of care<br>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. | Other: Current standard of care<br>* 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.<br>|
| Experimental: Current standard of care and convalescent plasma<br>Current standard of care and the infusion of two plasma units collected from two different COVID-19 convalescent patients. | Biological: Current standard of care and COVID-19 convalescent and vaccinated plasma<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with hospitalisation with progressive COVID-19 symptoms or death | Proportion of participants with (1) at least one overnight stay in hospital for progressive COVID-19 symptoms or (2) who died | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with hospitalisation for progressive COVID-19 symptoms or death |  | Day 14 | 
| Proportion of patients with hospitalisation for progressive COVID-19 symptoms requiring O2 support*, or death *O2 support: requirement based on O2 saturation level on room air <=93% or respiration rate >30 |  | Day 14 and Day 28 | 
| All-cause mortality |  | Day 28, 90, 180 | 
| Proportion of patients with supplemental oxygen |  | Day 14, 28 | 
| Proportion of patients with non-invasive ventilation |  | Day 14, 28 | 
| Proportion of patients with intubation and mechanical ventilation |  | Day 14, 28 | 
| Change in 10-point WHO Clinical Progression Scale score | The 10-point WHO clinical progression scale ranges from 0 to 10 (0: uninfected; 10: death) | Day 14, 28 | 
| Duration of hospital admission censored at 28 days |  | Day 28 | 
| Proportion of patients with admission to ITU |  | Day 14, 28 | 
| Duration of ITU admission censored at 28 days |  | Day 28 | 
| Proportion of patients with long COVID-19 symptoms and time to recovery |  | Day 28, 180 | 
| Health-related quality of life assessed by EQ-5D quality of life index | EQ-5D is one of the most widely used Health-related quality of life measure. EQ-5D questionnaires have 5 dimensions: Mobility, Human Autonomy, Current Activities, Pain & Discomfort, Anxiety & Depression, and all dimensions are described by 5 levels corresponding to patient response choices. A quality of life index ranging from less than 0 (worse than death) to 1 (full health) is derived from the answers to the questionnaires. | Day 28, 180 | 
| Number of Serious Adverse Events | Grade 3/4 adverse events and AE unexpected for their nature, onset, evolution, severity or frequency | 72 hours | 
| Number of Participants with arterial and venous thromboembolic events |  | Day 28, 90, 180 |