Convalescent Plasma for Severe COVID-19 Patients (PLACOVID)

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

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.

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Biological: Convalescent Plasma; Other: Best Supportive Care

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.

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90035-903
      • Hospital de Clínicas de Porto Alegre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Convalescent Plasma; 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; Fresh frozen plasma collected by apheresis from recovered COVID-19 patients added to best supportive care.; Other: Best Supportive Care; Any form of ventilatory support, extracorporeal membrane oxygenation, steroids, antibiotics and other supportive measures except for investigational interventions.; Other Names: Standard Treatment
ACTIVE_COMPARATOR: Best Supportive Care; Any form of ventilatory support, extracorporeal membrane oxygenation, steroids, antibiotics and other supportive measures except for investigational interventions.	Other: Best Supportive Care; Any form of ventilatory support, extracorporeal membrane oxygenation, steroids, antibiotics and other supportive measures except for investigational interventions.; Other Names: Standard Treatment

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Hospital de Clinicas de Porto Alegre
• Collaborators: Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul, Brazil; Instituto Cultural Floresta
• Investigators: Principal Investigator: Leo Sekine, PhD, Hospital de Clínicas de Porto Alegre; Study Director: Alexandre P Zavascki, PhD, Federal University of Rio Grande do Sul

Publications and helpful links

General Publications

• Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, Kong Y, Ren L, Wei Q, Mei H, Hu C, Tao C, Yang R, Wang J, Yu Y, Guo Y, Wu X, Xu Z, Zeng L, Xiong N, Chen L, Wang J, Man N, Liu Y, Xu H, Deng E, Zhang X, Li C, Wang C, Su S, Zhang L, Wang J, Wu Y, Liu Z. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA. 2020 Aug 4;324(5):460-470. doi: 10.1001/jama.2020.10044. Erratum In: JAMA. 2020 Aug 4;324(5):519.
• Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, Wang F, Li D, Yang M, Xing L, Wei J, Xiao H, Yang Y, Qu J, Qing L, Chen L, Xu Z, Peng L, Li Y, Zheng H, Chen F, Huang K, Jiang Y, Liu D, Zhang Z, Liu Y, Liu L. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020 Apr 28;323(16):1582-1589. doi: 10.1001/jama.2020.4783.
• Salazar E, Perez KK, Ashraf M, Chen J, Castillo B, Christensen PA, Eubank T, Bernard DW, Eagar TN, Long SW, Subedi S, Olsen RJ, Leveque C, Schwartz MR, Dey M, Chavez-East C, Rogers J, Shehabeldin A, Joseph D, Williams G, Thomas K, Masud F, Talley C, Dlouhy KG, Lopez BV, Hampton C, Lavinder J, Gollihar JD, Maranhao AC, Ippolito GC, Saavedra MO, Cantu CC, Yerramilli P, Pruitt L, Musser JM. Treatment of Coronavirus Disease 2019 (COVID-19) Patients with Convalescent Plasma. Am J Pathol. 2020 Aug;190(8):1680-1690. doi: 10.1016/j.ajpath.2020.05.014. Epub 2020 May 27.
• Joyner MJ, Bruno KA, Klassen SA, Kunze KL, Johnson PW, Lesser ER, Wiggins CC, Senefeld JW, Klompas AM, Hodge DO, Shepherd JRA, Rea RF, Whelan ER, Clayburn AJ, Spiegel MR, Baker SE, Larson KF, Ripoll JG, Andersen KJ, Buras MR, Vogt MNP, Herasevich V, Dennis JJ, Regimbal RJ, Bauer PR, Blair JE, van Buskirk CM, Winters JL, Stubbs JR, van Helmond N, Butterfield BP, Sexton MA, Diaz Soto JC, Paneth NS, Verdun NC, Marks P, Casadevall A, Fairweather D, Carter RE, Wright RS. Safety Update: COVID-19 Convalescent Plasma in 20,000 Hospitalized Patients. Mayo Clin Proc. 2020 Sep;95(9):1888-1897. doi: 10.1016/j.mayocp.2020.06.028. Epub 2020 Jul 19.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 16, 2020
• Primary Completion (ACTUAL): January 7, 2021
• Study Completion (ACTUAL): January 7, 2021

Study Registration Dates

• First Submitted: September 9, 2020
• First Submitted That Met QC Criteria: September 11, 2020
• First Posted (ACTUAL): September 14, 2020

Study Record Updates

• Last Update Posted (ACTUAL): February 9, 2021
• Last Update Submitted That Met QC Criteria: February 8, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: 2020-0158 (Other Identifier: M D Anderson Cancer Center)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No