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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05271929
Recruitment Status : Recruiting
First Posted : March 9, 2022
Last Update Posted : November 15, 2022
Sponsor:
Collaborator:
NHS Blood and Transplant
Information provided by (Responsible Party):
Deutsches Rotes Kreuz DRK-Blutspendedienst Baden-Wurttemberg-Hessen

Brief Summary:
  • 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)

Condition or disease Intervention/treatment Phase
COVID-19 Biological: Current standard of care and COVID-19 convalescent and vaccinated plasma Other: Current standard of care Phase 3

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 680 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomised Open-Label Trial of Early, Very High-Titre Convalescent Plasma Therapy in Clinically Vulnerable Individuals With Mild COVID-19
Actual Study Start Date : April 1, 2022
Estimated Primary Completion Date : March 10, 2024
Estimated Study Completion Date : September 10, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: 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.

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.


Experimental: Current standard of care and convalescent plasma
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
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.




Primary Outcome Measures :
  1. Proportion of participants with hospitalisation with progressive COVID-19 symptoms or death [ Time Frame: Day 28 ]
    Proportion of participants with (1) at least one overnight stay in hospital for progressive COVID-19 symptoms or (2) who died


Secondary Outcome Measures :
  1. Proportion of participants with hospitalisation for progressive COVID-19 symptoms or death [ Time Frame: Day 14 ]
  2. 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 [ Time Frame: Day 14 and Day 28 ]
  3. All-cause mortality [ Time Frame: Day 28, 90, 180 ]
  4. Proportion of patients with supplemental oxygen [ Time Frame: Day 14, 28 ]
  5. Proportion of patients with non-invasive ventilation [ Time Frame: Day 14, 28 ]
  6. Proportion of patients with intubation and mechanical ventilation [ Time Frame: Day 14, 28 ]
  7. Change in 10-point WHO Clinical Progression Scale score [ Time Frame: Day 14, 28 ]
    The 10-point WHO clinical progression scale ranges from 0 to 10 (0: uninfected; 10: death)

  8. Duration of hospital admission censored at 28 days [ Time Frame: Day 28 ]
  9. Proportion of patients with admission to ITU [ Time Frame: Day 14, 28 ]
  10. Duration of ITU admission censored at 28 days [ Time Frame: Day 28 ]
  11. Proportion of patients with long COVID-19 symptoms and time to recovery [ Time Frame: Day 28, 180 ]
  12. Health-related quality of life assessed by EQ-5D quality of life index [ Time Frame: Day 28, 180 ]

    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.


  13. Number of Serious Adverse Events [ Time Frame: 72 hours ]
    Grade 3/4 adverse events and AE unexpected for their nature, onset, evolution, severity or frequency

  14. Number of Participants with arterial and venous thromboembolic events [ Time Frame: Day 28, 90, 180 ]

Other Outcome Measures:
  1. Change in SARS-CoV-2 RNA level [ Time Frame: Day 3, 14, 28, 180 ]
    Polymerase chain reaction, Cycle Threshold value in oral or nose/throat swab samples at days 3, 14, 28 and 180 after randomisation

  2. Change in anti-SARS-CoV-2 spike antibody levels in blood [ Time Frame: Day 14, 28 ]
  3. SARS-CoV-2 whole-genome sequence analysis [ Time Frame: Day 1, 28 ]
  4. Proportion and clinical characteristics of patients with cultivable virus [ Time Frame: Day 28, 180 ]
  5. Virus sequence variation and cultivability over time, overall and in individuals receiving vs not receiving CCP [ Time Frame: Day 1, 28 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05271929


Contacts
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Contact: Eric Toussirot, MD, PhD +333 81 21 83 96‬ etoussirot@chu-besancon.fr

Locations
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France
CHU Besançon Not yet recruiting
Besançon, France, 25000
Contact: Eric Toussirot, MD, PhD         
Germany
Stauferklinikum Schwäbisch Gmünd Recruiting
Mutlangen, Baden-Wuerttemberg, Germany, 73527
Contact: Holger Herbart, Prof. Dr.         
Klinikum Stuttgart Not yet recruiting
Stuttgart, Baden-Wuerttemberg, Germany, 70174
Contact: Gregor Paul, Prof Dr. med         
Diakonie-Klinikum Stuttgart Recruiting
Stuttgart, Baden-Wuerttemberg, Germany, 70176
Contact: Jochen Greiner, Prof Dr med         
Uniklinikum Tübingen Not yet recruiting
Tübingen, Baden-Wuerttemberg, Germany, 72076
Contact: Tamam Bakchoul, Prof Dr med         
Institut für Klinische Transfusionsmedizin (IKT) Recruiting
Ulm, Baden-Wuerttemberg, Germany, 89081
Contact: Hubert Schrezenmeier, Prof Dr med.         
Uniklinikum Ulm Recruiting
Ulm, Baden-Wuerttemberg, Germany, 89081
Contact: Beate Grüner, Prof Dr med.         
Universitätsklinikum Brandenburg Not yet recruiting
Brandenburg an der Havel, Brandenburg, Germany, 14770
Contact: Markus Deckert, Prof Dr med         
Universitätsklinikum Frankfurt Not yet recruiting
Frankfurt, Hessen, Germany, 60590
Contact: Maria Vehreschild, Prof. Dr. med.         
Elblandkliniken Riesa Recruiting
Riesa, Sachsen, Germany, 01589
Contact: Joerg Schubert, Prof Dr med         
Charité Medizinische Klinik IV Recruiting
Berlin, Germany, 10117
Contact: Fabian Halleck, Dr. med.         
Klinikum Chemnitz gGmbH Recruiting
Chemnitz, Germany, 09116
Contact: Mathias Hänel, PD Dr.         
Netherlands
Erasmus Medical Center Recruiting
Rotterdam, Netherlands, 3000CA
Contact: Bart Rijnders, MD, PhD         
United Kingdom
NHS Blood and Transplant Not yet recruiting
Oxford, United Kingdom
Contact: Lise Estcourt, MD, PhD         
Sponsors and Collaborators
Deutsches Rotes Kreuz DRK-Blutspendedienst Baden-Wurttemberg-Hessen
NHS Blood and Transplant
Investigators
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Study Director: Pierre Tiberghien, MD, PhD Etablissement Français du Sang, La Plaine Saint-Denis, France
Principal Investigator: Eric Toussirot, MD, PhD Rheumatology department, CHU Besançon, France
Principal Investigator: Hubert Schrezenmeier, MD, PhD German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen
Principal Investigator: Lise Estcourt, MD, PhD NHS Blood and Transplant, Oxford, United Kingdom
Principal Investigator: David Roberts, MD, PhD NHS Blood and Transplant, Oxford, United Kingdom
Principal Investigator: Bart Rijnders, MD, PhD Erasmus Medical Center
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Responsible Party: Deutsches Rotes Kreuz DRK-Blutspendedienst Baden-Wurttemberg-Hessen
ClinicalTrials.gov Identifier: NCT05271929    
Other Study ID Numbers: COVIC-19
First Posted: March 9, 2022    Key Record Dates
Last Update Posted: November 15, 2022
Last Verified: November 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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COVID-19
Respiratory Tract Infections
Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases