Clinical trial NCT04547660: Convalescent Plasma for Severe COVID-19 Patients
Official title: Convalescent Plasma for Severe COVID-19 Patients: a Randomized, Open-label, Phase 3 Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Covid19
Lead sponsor: Hospital de Clinicas de Porto Alegre
Sponsor class: OTHER
Collaborators: name: Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul, Brazil
name: Instituto Cultural Floresta
First posted: 2020-09-14
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, open-label, phase 3, comparing best supportive care (BSC, no investigational drugs allowed) and convalescent plasma, along BSC.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Age equal to or greater than 18 yers;
2. Diagnosis of SARS-CoV-2 infection through nasal cavity or oropharynx swab RT-PCR;
3. 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;
4. Onset of symptoms in a period not exceeding 14 days.

Exclusion Criteria:

1. Impossibility for any reason to perform the first plasma infusion within 14 days of the onset of symptoms;
2. Use of immunosuppressants for other underlying diseases, except corticosteroids for the SARS-CoV-2, in the last 30 days before enrollment;
3. Pregnancy;
4. History of serious adverse reactions such as transfusion anaphylaxis;
5. Participation in another interventional clinical trial;
6. Disagreement of attending physician;
7. Disagreement of the patient or legal representative to participate in the study.

Primary outcomes:
measure: Clinical improvement
timeFrame: 28 days
Secondary outcomes:
measure: 6-point ordinal scale proportion at 14 days
timeFrame: 14 days from randomization
measure: 6-point ordinal scale proportion at 28 days
timeFrame: 28 days from randomization
measure: Overall mortality
timeFrame: 14 days
measure: Overall mortality
timeFrame: 28 days
measure: Days alive and free of respiratory support (DAFOR28)
timeFrame: 28 days
measure: Mechanical ventilation
timeFrame: 28 days
measure: PaO2/FiO2 ratio
timeFrame: At the 7th day of randomization
measure: Hospital stay
timeFrame: 28 days
measure: Lactate Dehydrogenase
timeFrame: Randomization day, Day 3, Day 7 and Day 14
measure: Troponin I
timeFrame: Randomization day, Day 3, Day 7 and Day 14
measure: C Reactive Protein
timeFrame: Randomization day, Day 3, Day 7 and Day 14
measure: D-Dimers
timeFrame: Randomization day, Day 3, Day 7 and Day 14
measure: Fibrinogen
timeFrame: Randomization day, Day 3, Day 7 and Day 14
measure: Prothrombin Time (PT)
timeFrame: Randomization day, Day 3, Day 7 and Day 14
measure: Activated Partial Thromboplastin Time (APTT)
timeFrame: Randomization day, Day 3, Day 7 and Day 14
measure: Tumor Necrosis Factor Alfa (TNF-Alfa)
timeFrame: Randomization day, Day 3, Day 7 and Day 14
measure: Interleukin-6 (IL-6)
timeFrame: Randomization day, Day 3, Day 7 and Day 14
measure: RT-PCR
timeFrame: At the 7th day of randomization (or at hospital discharge if earlier than 7 days)
measure: Sequential Organ Failure Assessment (SOFA) score
timeFrame: At the 7th day of randomization
measure: National Early Warning Score 2 (NEWS) 2
timeFrame: 7 and 14 days of randomization
measure: Safety and Adverse Events
timeFrame: 28 days
Other outcomes:
Locations:
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
state: Rio Grande Do Sul
Study officials:
affiliation: Hospital de Clínicas de Porto Alegre
name: Leo Sekine, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Federal University of Rio Grande do Sul
name: Alexandre P Zavascki, PhD
role: STUDY_DIRECTOR
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