Randomized clinical trial to evaluate safety and efficacy of convalescent plasma use among hospitalized patients with COVID-19 (PERUCONPLASMA): a structured summary of a study protocol for a randomized controlled trial
OBJECTIVES The general objective of this study is to test the hypothesis that administration of convalescent plasma from donors with previous diagnosis of severe COVID-19 pneumonia is safe and associated with a decrease in all-cause in-hospital mortality among hospitalized patients with COVID-19 at 30 days in comparison with standard treatment alone. The secondary objectives are as follows: (1) to assess the efficacy of convalescent plasma to reduce the length of hospitalization, (2) to assess the efficacy of convalescent plasma to reduce the length of ICU stay, and (3) to assess the efficacy of convalescent plasma on reducing the requirement of invasive mechanical ventilation or ICU stay. TRIAL DESIGN PERUCONPLASMA is a IIb phase open label, randomized, superiority clinical trial with 1:1 allocation taking place in real life routine clinical practice at public hospitals in Lima, Peru. Participants will be randomized to receive convalescent plasma along with local standard treatment or local standard treatment alone. After allocation, all participants will be followed for a total of 30 days or until hospital discharge, whichever occurs first. PARTICIPANTS The population for the study are patients with severe disease with a confirmed laboratory test for SARS-CoV-2 infection hospitalized in 3 tertiary-care hospitals in Lima, Peru. Subjects are eligible for the trial if they meet all of the following inclusion criteria: 1. Age 18 or older 2. Hospitalization due to COVID-19 with laboratory confirmation (either with serologic, molecular, or antigen test along with a compatible clinical presentation) 3. Severe or critical COVID-19 disease Severe illness was defined by 2 or more of the following: Respiratory rate of 22 or more Hypoxemia with oxygen saturation equal or less than 93% Abnormal blood gas analysis (PaO(2) < 60 mmHg, PaCO(2) > 50 mmHg, or Pa/FiO(2) < 300) Critical disease was defined by either: Mechanical ventilation requirement less than 72 h. Shock. 4. Capacity to provide informed consent (patient or patient's direct relative) 5. Availability of convalescent plasma units compatible with ABO blood type of the subject. EXCLUSION CRITERIA Subjects are not eligible for the trial if they meet any of the following criteria: 1. Contraindication for transfusion (e.g., prior anaphylaxis, congestive heart failure) 2. Hemodynamic instability (PA < 60 mmHg refractory to vasopressors) 3. Uncontrolled concomitant infections\ 4. Stupor or coma 5. Platelets < 50,000/μL or disseminated intravascular coagulation 6. Serum creatinine > 3.5 mg/dL or dialysis requirement 7. Total bilirubin > 6 mg/dL or jaundice of unknown etiology 8. Myocardial infarction or acute coronary syndrome 9. Active or recent (< 7 days) intracranial hemorrhage 10. Pregnancy Donors: The donors have to meet the following criteria: male between 30 and 60 years with a previous diagnosis of severe COVID-19-associated pneumonia within the last 3 months, with resolution of symptoms of at least 28 days. The rationale for including donors with severe disease is to maximize the probability of collecting convalescent plasma units with high titer of neutralizing antibodies, as the technology to measure this specific type of antibodies is not routinely available in Peru. Aliquots of plasma will be stored for future quantification of neutralizing antibodies. INTERVENTION AND COMPARATOR Convalescent plasma from donors with previous severe COVID-19 is the investigational medical product. The experimental group will receive 1 to 2 units of 200 to 250 ml of convalescent plasma along with local standard treatment. The control group will receive local standard treatment alone. The participants randomized to plasma will have evaluations at 6 h and 24 h to specifically evaluate possible post transfusion events. All the participants will be evaluated at day 3, day 7, and day 30 after enrolment. MAIN OUTCOMES Safety outcome: Incidence of serious adverse reactions related to convalescent plasma transfusion within 24 h after convalescent plasma administration. Efficacy outcomes: Mortality from any cause during hospitalization at 30 days post randomization. Length of hospitalization at 30 days post randomization or until hospital discharge. Duration of mechanical ventilation at 30 days post randomization or until hospital discharge. Length of hospitalization in an intensive care unit at 30 days post randomization or until hospital discharge. Exploratory: Oxygen requirement evolution at days 3 and 7. Score Sequential Organ Failure Assessment (SOFA) evolution at days 3 and 7. Dynamics of inflammatory marker (lymphocyte, C-reactive protein (CRP), D-dimer, lactate dehydrogenase (LDH)) evolution at days 3 and 7. Proportion of patients progressing to multi-organ failure at 30 days post randomization or until hospital discharge. Proportion of transfusion related adverse reactions at 30 days post randomization or until hospital discharge. RANDOMIZATION Randomization will be carried out within the electronic case report form (eCRF) in 1:1 ratio (receive plasma/control) in a randomization process established by blocks of size 2, 4, and 6. Allocation to the treatment arm of an individual patient will not be available to the investigators before completion of the whole randomization process. Randomization blocks will be performed with "ralloc", Stata's randomization process v.16.0. Randomization through the eCRF will be available 24 h every day. BLINDING (MASKING): Both the participants and study staff will be aware of the allocated intervention. Blinded statistical analysis will be performed. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): The sample size was calculated using the Fleiss formula with continuity correction to detect a mortality reduction from 50 to 20% between the two treatment arms with a confidence level of 95% and a power of 80%. Based on this information, a total of 45 patients per arm would be needed. After adjustment for a drop-out rate of 10% after enrolment, a total of 50 patients per arm (100 patients in total) will be enrolled. TRIAL STATUS Current protocol version: 5.0 dated January 04, 2021. Recruitment started on September 21, 2020, and is expected to finish by the end of March 2021. TRIAL REGISTRATION Peruvian Register of Clinical Trials (REPEC) ID: PER-016-20, registered on June 27, 2020. Clinicaltrials.gov ID: NCT04497324 , registered on August 4, 2020. FULL PROTOCOL The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.
Dynamics of antibodies to SARS-CoV-2 in convalescent plasma donors
Clinical & Translational Immunology. 2021;10(5):e1285
OBJECTIVES Characterisation of the human antibody response to SARS-CoV-2 infection is vital for serosurveillance purposes and for treatment options such as transfusion with convalescent plasma or immunoglobulin products derived from convalescent plasma. In this study, we longitudinally and quantitatively analysed antibody responses in RT-PCR-positive SARS-CoV-2 convalescent adults during the first 250 days after onset of symptoms. METHODS We measured antibody responses to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and the nucleocapsid protein in 844 longitudinal samples from 151 RT-PCR-positive SARS-CoV-2 convalescent adults. With a median of 5 (range 2-18) samples per individual, this allowed quantitative analysis of individual longitudinal antibody profiles. Kinetic profiles were analysed by mixed-effects modelling. RESULTS All donors were seropositive at the first sampling moment, and only one donor seroreverted during follow-up analysis. Anti-RBD IgG and anti-nucleocapsid IgG levels declined with median half-lives of 62 and 59 days, respectively, 2-5 months after symptom onset, and several-fold variation in half-lives of individuals was observed. The rate of decline of antibody levels diminished during extended follow-up, which points towards long-term immunological memory. The magnitude of the anti-RBD IgG response correlated well with neutralisation capacity measured in a classic plaque reduction assay and in an in-house developed competitive assay. CONCLUSION The result of this study gives valuable insight into the long-term longitudinal response of antibodies to SARS-CoV-2.
A matched cohort study of convalescent plasma therapy for COVID-19
Journal of Clinical Apheresis. 2021
INTRODUCTION COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a public health crisis. Prior studies demonstrated successful use of convalescent plasma therapy for treatment of other viral illnesses. Our primary objective was to evaluate treatment efficacy of convalescent plasma in patients with COVID-19. MATERIALS AND METHODS In this retrospective matched cohort study, we enrolled recipients of convalescent plasma collected from donors recovered from laboratory-confirmed SARS-CoV-2 infection under the single patient eIND process. We individually matched 35 cases with 61 controls based on age, gender, supplemental oxygen requirements, and C-reactive protein level at the time of hospital admission. We compared the outcomes of in-hospital mortality and hospital length of stay between the groups. RESULTS In-hospital mortality was 20% among the cases and 24.6% among the controls (P = .61). A multivariable logistic regression model that included age, gender, duration of symptoms, need for mechanical ventilation, and pharmacologic interventions revealed no significant difference in mortality by study group (P = .71). The median length of stay was significantly greater among convalescent plasma recipients compared with controls, 10 (IQR, 6-17) vs 7 (IQR, 4-11) days, P < .01. The difference was not significant after controlling for covariates (P > .1). CONCLUSIONS We did not find convalescent plasma reduced in-hospital mortality in our sample, nor did it reduce length of stay. Further investigation is warranted to determine the efficacy of this treatment in patients with COVID-19, particularly early in the disease process.
Potential use of convalescent plasma for SARS-CoV-2 prophylaxis and treatment in immunocompromised and vulnerable populations
Expert Review of Vaccines. 2021
INTRODUCTION : The ongoing SARS-CoV-2 pandemic is a serious threat for the health of immunocompromised patients. Among neutralizing antibody-based therapeutics, convalescent plasma containing polyclonal anti-SARS-CoV-2 immunoglobulins has promising results in both congenital and iatrogenic immunodeficiencies in oncohematological and transplant patients. AREAS COVERED : This article discusses case reports, case series and controlled studies detailing the efficacy of convalescent plasma in immunocompromised patients. EXPERT OPINION : Convalescent plasma, when administered at high neutralizing antibody titers, is a safe and effective treatment for frail immunocompromised patients. Genetic monitoring of refractory patients is recommended to intercept intra-host emergence of SARS-CoV-2 variants.
Patient-blood management for COVID19 convalescent plasma therapy: should donor-recipient differences in concentration and affinity of neutralizing antibodies drive use?
Clinical Microbiology and Infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2021
BACKGROUND COVID19 convalescent plasma (CCP) is being extensively investigated as a treatment, with mixed results to date. Overall, there has been a generalized lack of appropriateness in prescriptions, which is termed patient-blood management in the field of transfusion medicine. OBJECTIVES We aimed at dissecting study design variables which could affect clinical outcome after CCP therapy. We focus here on variables such as pretransfusion antibody testing in recipients, dose adjustements, and antibody affinity measurements. SOURCES We searched PubMed and preprint servers for relevant preclinical and clinical studies discussing each of these variables in the field of CCP therapy. CONTENT We show evidences on how neglecting those variables has affected the outcomes of the vast majority of CCP clinical trials to date.. IMPLICATIONS A better understanding of such variables will improve the design of the next generation of CCP clinical trials. This will likely lead to better clinical outcomes and minimize risks from subneutralizing neutralizing antibody doses.
COVID19 immune plasma donation after vaccination: pros and cons
Transfusion and Apheresis Science : Official Journal of the World Apheresis Association : Official Journal of the European Society for Haemapheresis. 2021;:103151
COVID-19 Convalescent Plasma: from donation to treatment - A Systematic Review & Single Center Experience
Missouri medicine. 2021;118(1):74-80
Convalescent plasma is an old treatment for a new disease. The coronavirus disease 2019 (COVID-19) pandemic caused the analysis of convalescent plasma to reemerge as a possible treatment. First, a systematic review summarizes the available research examining the use of convalescent plasma for the treatment of patients with COVID-19. Second, we describe our experience in establishing a single-center convalescent plasma donation program.
Convalescent hyperimmune plasma for chemo-immunotherapy induced immunodeficiency in COVID-19 patients with hematological malignancies
Leukemia & Lymphoma. 2021;:1-9
During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, patients with defective immunity after chemo-immunotherapy due to hematological disorders showed prolonged symptoms and worse prognosis of coronavirus disease-2019 (COVID-19) pneumonia, probably due to inadequate adaptive immune response and noneffective viral clearance. We describe a single-center series of hematological immunocompromised patients undergoing passive immunization with hyperimmune plasma for persistent COVID-19 symptoms. In all cases, such treatment was well tolerated and contributed to clinical and radiological improvement and recovery; viral clearance was also achieved in a patients' subset. Although requiring further investigation, these results suggest a specific role for hyperimmune plasma administration in hematological patients.
Impact of Pathogen-Reduction Technologies on Covid19 Convalescent Plasma Potency
Transfusion Clinique Et Biologique : Journal De La Societe Francaise De Transfusion Sanguine. 2021
Pathogen reduction technologies (PRT) have been recommended by many regulatory authorities to minimize the residual risk of transfusion-transmitted infections associated with COVID19 convalescent plasma. While its impact on safety and its cost-effectiveness are nowadays well proven, there is theoretical concern that PRT could impact efficacy of convalescent plasma by altering concentration and/or function of the neutralizing antibodies (nAb). We review here the evidence supporting a lack of significant detrimental effect from PRTs on nAbs.
Rapidly Establishing a Hospital-Based Convalescent Plasma Collection Center With the Alyx Apheresis Collection Device
Academic Pathology. 2021;8:2374289520987236
The effort to collect convalescent plasma from individuals who recovered from COVID-19 began in earnest during the spring of 2020. Either whole blood or apheresis donations were obtained, the latter yielding higher numbers of units per donor per collection and more frequent collections. The NorthShore University HealthSystem blood donor center purchased 2 Alyx (Fresenius Kabi) apheresis plasma collection devices and quickly implemented them in order to collect COVID-19 convalescent plasma. Apheresis-experienced and inexperienced phlebotomists operated the instruments. Donors were collected >14 days from symptom resolution and all donors were negative by SARS-CoV-2 nasopharyngeal swab. Both internal metrics of performance as well as a post donation survey were used to evaluate the feasibility implementing this collection program. During the first 100 days of the collection program, 650 plasma units were collected. In particular, during the first week of the program, 38 units were collected and distributed to hospitals under the emergency investigational new drug and expanded access program. Fifty-one donors (15%) were deferred due to vital signs out of range or donor screening questions. Thirty-one donors (10%) were deferred due to positive nasopharyngeal swab. Lower than target yield occurred in 16.6% of collections due to donor reactions or flow errors. Donors rated the overall program lower, but not the staff, when they reported symptoms related to collection. In conclusion, a hospital-based apheresis convalescent plasma collection program can be rapidly implemented. Donor reaction rates and vein infiltration rates should be carefully monitored for each phlebotomist.