Convalescent Plasma Therapy vs. SOC for the Treatment of COVID-19 in Hospitalized Patients

Study Overview
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Brief Summary
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A total of 278 patients are planned. All patients will be in an early-stage of COVID-19. They must be adults and hospitalized. In this study, all participating patients will receive the standard treatment provided according to the current treatment protocols for coronavirus disease. In addition to this treatment, each patient will be randomly assigned to receive additional treatment with convalescent plasma transfusion (CP; blood plasma from patients who have been cured of coronavirus), or continue with standard treatment but without adding transfusion. 50% of the chances of additional treatment with CP, and 50% of the chances of receiving only the standard treatment for coronavirus. The duration of the study shall be one month from the assignment of the treatment. The patient and the doctor will know the treatment assigned.

Detailed Description
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A multi-center, randomized, clinical trial with two arms to study the efficacy and safety of passive immunotherapy with CP compared to a control of standard of care (SOC). All trial participants will receive SOC: Treatment arm: Pathogen-reduced CP from patients recovered from COVID-19, whom, for the purpose of this trial, are herein designated as donors. Control arm: SOC for COVID-19. Randomization among the two arms will be 1:1 and will be stratified per center. Of note, in the current status of a worldwide pandemic for which we have no approved vaccines or drugs, for the purpose of this trial SOC would also accept any drugs that are being used in clinical practice (e.g. lopinavir/ritonavir; darunavir/cobicistat; hydroxy/chloroquine, tocilizumab, etc.), other than those used as part of another clinical trial. The study is planned with a sequential design. Interim analyses: comprehensive safety data monitoring analyses will be conducted when 20%, 40%, 60% and 80% of patients, or at the discretionary DSMB criteria when needed. A DSMB charter will be set before the trial initiation where criteria for prematurely stopping the trial due to safety issues will be set. Interim analyses will be predefined upfront based on the DSMB recommendations.

Official Title
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Multi-center, Randomized Clinical Trial of Convalescent Plasma Therapy Versus Standard of Care for the Treatment of COVID-19 in Hospitalized Patients

Conditions
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COVID-19

Intervention / Treatment
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* Other: Blood and derivatives.
* Drug: Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent prior to performing study procedures. Witnessed oral consent will be accepted in order to avoid paper handling. Written consent by patient or representatives will be obtained as soon as possible. Male or female adult patient ≥18 years of age at time of enrolment. Has laboratory-confirmed SARS-CoV-2 infection as determined by PCR in naso/oropharyngeal swabs or any other relevant specimen in the ongoing COVID-19 symptomatic period. Alternative test (i.e antigenic tests) are also acceptable as laboratory confirmation if their adequate specificity has been accepted by the sponsor. Patients requiring hospitalization for COVID-19 without mechanical ventilation (invasive or non-invasive) or high flow oxygen devices and at least one of the following: Radiographic evidence of pulmonary infiltrates by imaging (chest x-ray, CT scan, etc.), OR Clinical assessment (evidence of rales/crackles on exam) AND SpO2 ≤ 94% on room air that requires supplemental oxygen. No more than 7 days between the onset of symptoms (fever or cough) and treatment administration day. Exclusion Criteria: Requiring mechanical ventilation (invasive or non-invasive) or high flow oxygen devices. More than 7 days since symptoms (fever or cough). Participation in any other clinical trial of an experimental treatment for COVID-19. In the opinion of the clinical team, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments. Any incompatibility or allergy to the administration of human plasma. Stage 4 severe chronic kidney disease or requiring dialysis (i.e. eGFR <30).

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
Interventional Model Description: 1:1 ratio for CP: Control arm. Also, approximately 140-200 CP donors.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>Pathogen-reduced CP from patients recovered from COVID-19, whom, for the purpose of this trial, are herein designated as donors. | Other: Blood and derivatives.<br>* Administration of fresh plasma from donor immunized against COVID-19<br>* Other names: Convalescent Plasma from patients recovered from COVID-19;|
| Active Comparator: Control Arm<br>Standard of Care (SOC) for COVID-19 | Drug: Standard of Care<br>* Standard of care for the treatment of COVID-19 in hospitalized patients<br>* Other names: SOC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Category Changes in the 7-Ordinal Scale | Proportion of patients in categories 5, 6 or 7 of the 7-point ordinal scale at day 15 7- Ordinal scale: Not hospitalized, no limitations on activities. Not hospitalized, limitation on activities. Hospitalized, not requiring supplemental oxygen. Hospitalized, requiring supplemental oxygen. Hospitalized, on non-invasive ventilation or high flow oxygen devices. Hospitalized, on invasive mechanical ventilation or ECMO. Death. | 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to category 5, 6 or 7 of the  7-Ordinal scale | Time to change from baseline category to worsening into 5,6 or 7 categories of the 7-Ordinal scale | 29 days | 
| Time to an improvement of one category from admission in the 7-Ordinal scale | Time to an improvement of one category from admission in the 7-Ordinal scale | 29 days | 
| Status at day 30 in the 11-Ordinal scale | Status at day 30 in the 11-Ordinal scale 11-Ordinal scale : 0. Uninfected ; no viral RNA detected. Asymptomatic; viral RNA detected, limitation on activities. Symptomatic; independent Symptomatic; assistance needed Hospitalized, no oxygen therapy. Hospitalized, oxygen by mask or nasal prongs Oxygen by mask or nasal prongs Intubation and mechanical ventilation, pO2/FiO2 ≥150 or SpO2/FiO2 ≥200 Mechanical ventilation pO2/FIO2 <150 (SpO2/FiO2 <200) or vasopressors Mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis, or ECMO Dead | 30 days | 
| Status at day 15 and 30 in the 11-Ordinal scale | Status at day 15 and 30 in the 11-Ordinal scale Status at day 15 and 30 in the 11-Ordinal scale | 30 days | 
| Time to first deterioration | Time to first deterioration | 60 days | 
| Mean change in the ranking in the 7-Ordinal scale from baseline to days 3,5,8,11,15,29 and 60 | Mean change in the ranking in the 7-Ordinal Scale from baseline to days 3,5,8,11,15,29 and 60 | 60 days | 
| Mean change in the ranking in the 11-Ordinal scale from baseline to days 3,5,8,11,15,29 and 60. | Mean change in the ranking in the 11- Ordinal scale from baseline to days 3,5,8,11,15,29 and 60. | 60 days | 
| Mortality of any cause at 15 days | Rate of mortality of any cause within first 15 days. | 15 days | 
| Mortality of any cause at 28 days (day 29) | Rate of mortality of any cause within first 28 days. | 28 days (day 29) | 
| Mortality of any cause at 60 days | Rate of mortality of any cause within first 60 days. | 60 days | 
| Oxygenation free days | days free from oxygen supplementation | 29 days | 
| Ventilator free days | days free from mechanical ventilation | 29 days | 
| Duration of hospitalization (days) | days of hospitalization | 60 days | 
| Infusion-related adverse events | Infusion-related adverse events Cumulative incidence of serious adverse events (SAEs) Cumulative incidence of Grade 3 and 4 adverse events (AEs). | 60 days | 
| Incidence of Treatment-Emergent Adverse Events | cumulative incidence of Grade 3 and 4 adverse events (AEs) Cumulative incidence of serious adverse events (SAEs) Cumulative incidence of Grade 3 and 4 adverse events (AEs). | 60 days | 
| Antibodies levels in CP donors recovered from COVID-19 | Quantitative total antibodies and neutralizing antibody activity against SARSCoV-2 in the sera from donors and patients using viral pseudotypes | 3 months | 
| Viral load | Change in PCR for SARS-CoV-2 in naso/oropharyngeal swabs at baseline and at discharge | Days 1,3,5,8,11,15, 29 and 60 | 
| Viral load | Change in PCR for SARS-CoV-2 in blood on Days 3,5,8,11,15,29 and 60 (while hospitalized) until two of them are negative consecutively | Days 1,3,5,8,11,15,29 and 60 | 
| Incidence of thrombotic arterial events | incidence of thrombotic arterial events | 60 days | 
| Incidence of thrombotic venous events | incidence of thrombotic venous events | 60 days | 
| rate of rehospitalizations | rehospitalizations | 60 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Coronavirus, SARS-CoV-2, Convalescent Plasma, SOC, CP