Convalescent Plasma for Severe COVID-19 Patients

Study Overview
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Brief Summary
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Plasma, the supernatant part of blood, contains a variety of different proteins, including immunoglobulins. These proteins, also called antibodies, are directed to previous foreign infecting organisms, such as virus, bacteria or parasites. Patients recovering from SARS-Cov-2 infection may develop protective antibodies which can prevent reinfection with the same agent or similar organisms with shared molecular structures. Those antibodies may be transferred to other patients through collection of such convalescent plasma from recovered donors and its transfusion to ill patients. In this research, the primary hypothesis is that those antibodies can exert passive immunization and help ameliorate symptoms from COVID-19 (Coronavirus Disease 2019), resulting in higher clinical improvement rates at day 28, especially when administered early in the infection course.

Detailed Description
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This is a randomized, open-label, phase 3 clinical trial on the use of convalescent plasma for severe COVID-19 patients. In this research, we are going to assess efficacy and safety of convalescent plasma in the treatment of severely compromised COVID-19 patients. Convalescent plasma will be collected from recovered COVID-19 patients, who will be recruited as plasma donors and will be submitted to apheresis (with minimum interval of 14 days) to obtain two aliquots of 300 ml of convalescent plasma, which will be frozen at -80 and stored at -20 to -30 degrees Celsius. Enrolled patients will be randomized based on a concealed sequential allocation list by an independent researcher which will not be aware of patients characteristics, and stratified by COVID-19 severity (severe or life-threatening). There will be two arms of study, intervention or control group, and patients will be followed up for the next 28 days for clinical and laboratory outcomes such as improvement of disease status (measured by a 6-point ordinal severity scale); mechanical ventilation, intensive care unit (ICU) and total hospital stay period; cytokine levels (IL-6 and TNF-alfa) and several inflammatory, cellular injury and coagulation parameters. Intervention was conceived as two infusions of 300 ml of convalescent plasma, 2 days apart. Control group will receive full supportive treatment but will not be allowed to receive other investigational drugs. Sample size was calculated to a total of 160 patients, with a 1:1 randomization proportion between groups. This amount would be capable to detect an 18% or higher difference in the proportion of clinical improvement at 28 days of enrollment between intervention and control groups, with an alfa error of 0.05 and a statistical power of 0.8.

Official Title
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Convalescent Plasma for Severe COVID-19 Patients: a Randomized, Open-label, Phase 3 Trial

Conditions
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Covid19

Intervention / Treatment
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* Biological: Convalescent Plasma
* Other: Best Supportive Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age equal to or greater than 18 yers; Diagnosis of SARS-CoV-2 infection through nasal cavity or oropharynx swab RT-PCR; Severe COVID-19 defined by the presence of at least 1 of the following: A. Respiratory rate> 30 breaths per minute in room air; B. Oxygen saturation (O2) ≤93% in room air; C. PaO2 / FiO2 ratio ≤300; D. Need for supplemental O2 to maintain O2 saturation> 95%; E. Need for therapy with supplemental O2 by high flow catheter or non-invasive ventilation or invasive mechanical ventilation; Onset of symptoms in a period not exceeding 14 days. Exclusion Criteria: Impossibility for any reason to perform the first plasma infusion within 14 days of the onset of symptoms; Use of immunosuppressants for other underlying diseases, except corticosteroids for the SARS-CoV-2, in the last 30 days before enrollment; Pregnancy; History of serious adverse reactions such as transfusion anaphylaxis; Participation in another interventional clinical trial; Disagreement of attending physician; Disagreement of the patient or legal representative to participate in the study.

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: Randomized, open-label, phase 3, comparing best supportive care (BSC, no investigational drugs allowed) and convalescent plasma, along BSC.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Convalescent Plasma<br>Transfusion of 2 aliquots of 300 ml of frozen convalescent plasma, 2 days apart, thawed at 37 degrees Celsius before infusion. Best supportive care except for investigational interventions. | Biological: Convalescent Plasma<br>* Fresh frozen plasma collected by apheresis from recovered COVID-19 patients added to best supportive care.<br>Other: Best Supportive Care<br>* Any form of ventilatory support, extracorporeal membrane oxygenation, steroids, antibiotics and other supportive measures except for investigational interventions.<br>* Other names: Standard Treatment;|
| Active Comparator: Best Supportive Care<br>Any form of ventilatory support, extracorporeal membrane oxygenation, steroids, antibiotics and other supportive measures except for investigational interventions. | Other: Best Supportive Care<br>* Any form of ventilatory support, extracorporeal membrane oxygenation, steroids, antibiotics and other supportive measures except for investigational interventions.<br>* Other names: Standard Treatment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical improvement | Improvement of 2 points from randomization in a 6-point ordinal severity scale (6 points, death; 5 points, hospitalization plus extracorporeal membrane oxygenation (ECMO) or invasive mechanical ventilation; 4 points, hospitalization plus noninvasive ventilation or high-flow supplemental oxygen; 3 points, hospitalization plus supplemental oxygen (not high-flow or noninvasive ventilation); 2 points, hospitalization with no supplemental oxygen; 1 point, hospital discharge) | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-point ordinal scale proportion at 14 days | Proportions of individuals classified in each 6-point ordinal scale strata | 14 days from randomization | 
| 6-point ordinal scale proportion at 28 days | Proportions of individuals classified in each 6-point ordinal scale strata | 28 days from randomization | 
| Overall mortality | Death from any cause after randomization | 14 days | 
| Overall mortality | Death from any cause after randomization | 28 days | 
| Days alive and free of respiratory support (DAFOR28) | Days free of respiratory support during follow up | 28 days | 
| Mechanical ventilation | Duration of invasive ventilatory support (for those who received mechanical ventilation) | 28 days | 
| PaO2/FiO2 ratio | PaO2/FiO2 ratio at 7 days of follow up | At the 7th day of randomization | 
| Hospital stay | Time from randomization to hospital discharge (for 28-day survivors) | 28 days | 
| Lactate Dehydrogenase | LDH (U/L) | Randomization day, Day 3, Day 7 and Day 14 | 
| Troponin I | Troponin I (pg/mL) | Randomization day, Day 3, Day 7 and Day 14 | 
| C Reactive Protein | CRP (mg/L) | Randomization day, Day 3, Day 7 and Day 14 | 
| D-Dimers | D-Dimers (mcg/mL) | Randomization day, Day 3, Day 7 and Day 14 | 
| Fibrinogen | Fibrinogen (mg/dL) | Randomization day, Day 3, Day 7 and Day 14 | 
| Prothrombin Time (PT) | PT (seconds) | Randomization day, Day 3, Day 7 and Day 14 | 
| Activated Partial Thromboplastin Time (APTT) | APTT (seconds) | Randomization day, Day 3, Day 7 and Day 14 | 
| Tumor Necrosis Factor Alfa (TNF-Alfa) | TNF-Alfa (pg/mL) | Randomization day, Day 3, Day 7 and Day 14 | 
| Interleukin-6 (IL-6) | IL-6 (pg/mL) | Randomization day, Day 3, Day 7 and Day 14 | 
| RT-PCR | Nasal and Oropharyngeal Swab RT-PCR | At the 7th day of randomization (or at hospital discharge if earlier than 7 days) | 
| Sequential Organ Failure Assessment (SOFA) score | SOFA score at 7 days of randomization (ranges from 0 to 24, prognosis worsens with higher score values) | At the 7th day of randomization | 
| National Early Warning Score 2 (NEWS) 2 | Change in NEWS 2 from randomization at 7 days and 14 days (ranges from 0 to 20, prognosis worsens with higher score values) | 7 and 14 days of randomization | 
| Safety and Adverse Events | CTCAE grade 3-4 events during follow up | 28 days |