Efficacy of CONvalescent Plasma in Patients With COVID-19 Treated With Mechanical Ventilation

Study Overview
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Brief Summary
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The principal objective of the CONFIDENT trial is to assess the efficacy of two units (400-500 mL in total) of convalescent plasma, as compared to Standard of Care (SoC), to reduce day-28 mortality in patients with SARS-CoV-2 pneumonia who require mechanical ventilation.

Detailed Description
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Design : multicenter randomized openlabel, phase II trial. Number of patients to include : 500 (250 with plasma, 250 without plasma). The principal objective is to assess the efficacy of the treatment to reduce day-28 mortality in patients with SARS-CoV-2 pneumonia who require mechanical ventilation. Hypothesis: Passive immunization with plasma collected from patients having contracted COVID-19 and developed specific antibodies may alleviate symptoms and viral load of SARS-CoV-2 and reduce mortality. The patients will receive currently accepted standard of care for both COVID-19 and usual organ dysfunctions observed in such cases. half the patients will be administered either Convalescent plasma, depending on the randomization process. All patients will be followed-up for one year after inclusion. The study will be considered either positive or negative, based on the principal objective. This means that the product convalescent plasme will be considered effective if mortality at day 28 is lower is patients treated with convalescent plasma than without it. The follow-up will allow to assess a series of secondary objectives, addressing the evolution of organ failures, viral infection, inflammatory response and long-term physical of psychological impact of COVID-19. Interim analyses will be performed every 100 patients included in order to stop the trial if an exceptionally good or bad result is observed, to prevent using or not using the product appropriately in further patients. These analyses will be supervised by an independent committee. The choice to include only those patients under mechanical ventilation for severe respiratory failure makes this study different from other trials testing convalescent plasma, as most trial include less severe patients.

Official Title
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A Multicenter Randomized Trial to Assess the Efficacy of CONvalescent Plasma Therapy in Patients With Invasive COVID-19 and Acute Respiratory Failure Treated With Mechanical Ventilation: the CONFIDENT Trial

Conditions
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Covid19, Mechanical Ventilation Complication, Corona Virus Infection, Respiratory Failure, SARS (Severe Acute Respiratory Syndrome)

Intervention / Treatment
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* Biological: Convalescent Plasma
* Other: Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age at least 18 years hospitalization in an intensive care unit participating to the study medical diagnosis with SARS-CoV-2 pneumonia as defined by both: extended interstitial pneumonia on CT scan or a chest X-ray, consistent with viral pneumonia, within 10 days prior to inclusion Positive result of SARS-CoV-2 PCR test, or any emerging and validated diagnostic laboratory test for COVID-19, within 15 days prior to inclusion under mechanical ventilation administered through an endotracheal tube, for less than 5 days prior Clinical Frailty Scale < 6. written consent of the patient, or - if impossible - of a relative acting as the legal representative, or - if impossible - of a physician from a non-participating department of the same hospital acting as an impartial witness . Exclusion Criteria: Pregnancy Prior episode of transfusion-related side effect Medical decision to limit therapy Current participation in another trial testing a COVID-19 therapy

Ages Eligible for Study
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Minimum Age: 18 Years

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 |
| --- | --- |
| Experimental: Convalescent Plasma<br>2 units of plasma ( 400-500ml) from 2 different donnors duration of treatment =2 h | Biological: Convalescent Plasma<br>* 2 units of convalescent plasma<br>|
| Other: Standard of care<br>Standard of care according the last gold standards | Other: Standard of Care<br>* Gold Standards<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vital status | dead or alive | at day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| day 90 mortality | dead or alive | at day 90 | 
| number of ventilator-free days at day 28 | to assess the ventilator free days | at day 28 | 
| number of renal replacement therapy free days at day 28 | to assess the number of renal replacement therapy free days | at day 28 | 
| number of vasopressors free-days at day 28 | to assess the number of vasopressors free-days | at day 28 | 
| use of ECMO before day 28 | to assess if ECMO was required | till day 28 | 
| value of the SOFA score at days 7, 14 and 28 | to assess the value of SOFA score | Day 1, 7, 14, 28 | 
| changes in SOFA scores (delta SOFA) over 7, 14 and 28 days | to assess the changes in SOFA scores (delta SOFA) | Day 7, 14 and 28 days | 
| assessment of the SARS-CoV-2 viral load | assessment of the SARS-CoV-2 viral load, expressed as cycle threshold, [2] in the tracheal aspirates (for intubated patients) or nasopharyngeal swabs (for extubated patients) at days 7, 14 and 28 | Days 7, 14 and 28 | 
| blood C reactive protein (CRP) concentration | to assess the concentrations of C reactive protein (CRP) | Days 7, 14 and 28 | 
| ferritin concentration | to assess the concentration of ferritin | Days 7, 14 and 28 | 
| lymphocyte count | to assess the count of lymphocyte | Days 7, 14 and 28 | 
| length of stay in the acute care hospital | to assess the lenght of stay in the acute care | through study completion, 1 year | 
| location of the patient | to assess the location of the patient : acute care hospital, post acute care hospital, long-term residency, home | Day 90 | 
| Katz Index of independence in Activity Day Living functional score | to assess the Activity Day Living functional Min value: 0 = Low (patient very dependent) Max value: 6 = High (patient independent) | Day 90 and 365 | 
| Hospital Anxiety and Depression Scale (HADS) | to evaluate the anxiety-depression For each item 0-7 : Normal 8-10 : Bordeline abnormal (borderline case) 11-21 : Abnormal case | Day 90 and 365 | 
| Quality of life scale EQ-5D-5L | The EQ-5D-5L is composed of - the EQ-5D-5L descriptive system and the EQ Visual Analogue scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self care, usual activities, pain/discomfort, anxiety/depression). Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Each level corresponds to 1-digit number expressing the level selected for that dimension. The EQ VAS corresponds to a 20 cm vertical, visual analogue scale raging from 'the best health you can imagine' to 'the worst health you can imagine'. | Day 90 and 365 | 
| Transfusion related adverse events | to assess the transfusion related adverse events | till 28 days | 
| Determine the type of concommittent inflammatory response | assess clusters based on the profile of cytokines, chemokines and cell adhesion markers | till 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Covid 19, Convalescent plasmatherapy, SARS Cov-2 pneumonia