Convalescent plasma transfusion therapy in severe COVID-19 patients- a safety, efficacy and dose response study: A structured summary of a study protocol of a phase II randomized controlled trial

Abstract

Objectives General: To assess the safety, efficacy and dose response of convalescent plasma (CP) transfusion in severe COVID-19 patients Specific: a. To identify the appropriate effective dose of CP therapy in severe patients b. To identify the efficacy of the therapy with their end point based on clinical improvement within seven days of treatment or until discharge whichever is later and in-hospital mortality c. To assess the clinical improvement after CP transfusion in severe COVID-19 patients d. To assess the laboratory improvement after CP transfusion in severe COVID-19 patients Trial Design This is a multicentre, multi-arm phase II Randomised Controlled Trial. Participants Age and sex matched COVID-19 positive (by RT-PCR) severe cases will be enrolled in this trial. Severe case is defined by the World Health Organization (W.H.O) clinical case definition. The inclusion criteria are 1. Respiratory rate > 30 breaths/min; PLUS 2. Severe respiratory distress; or SpO2 ≤ 88% on room air or PaO2/FiO2≤ 300 mm of Hg, PLUS 3. Radiological (X-ray or CT scan) evidence of bilateral lung infiltrate, AND OR 4. Systolic BP < 90 mm of Hg or diastolic BP <60 mm of Hg. AND/OR 5. Criteria 1 to 4 AND or patient in ventilator support Patients’ below18 years, pregnant and lactating women, previous history of allergic reaction to plasma, patients who have already received plasma from a different source will be excluded. Patients will be enrolled at Bangabandhu Sheikh Mujib Medical University (BSMMU) hospital, Dhaka medical college hospital (DMCH) and Mugda medical college hospital (MuMCH). Apheretic plasma will be collected at the transfusion medicine department of SHNIBPS hospital, ELISA antibody titre will be done at BSMMU and CMBT and neutralizing antibody titre will be checked in collaboration with the University of Oxford. Patients who have recovered from COVID-19 will be recruited as donors of CP. The recovery criteria are normality of body temperature for more than 3 days, resolution of respiratory symptoms, two consecutively negative results of sputum SARS-CoV-2 by RT-PCR assay (at least 24 hours apart) 22 to 35 days of post onset period, and neutralizing antibody titre ≥ 1:160. Intervention and comparator This RCT consists of three arms, a. standard care, b. standard care and 200 ml CP and c. standard care and 400 ml CP. Patients will receive plasma as a single transfusion. Intervention arms will be compared to the standard care arm. Main outcomes The primary outcome will be time to clinical improvement within seven days of treatment or until discharge whichever is later and in-hospital mortality. The secondary outcome would be improvement of laboratory parameters after therapy (neutrophil, lymphocyte ratio, CRP, serum ferritin, SGPT, SGOT, serum creatinine and radiology), length of hospital stay, length of ICU stay, reduction in proportion of deaths, requirement of ventilator and duration of oxygen and ventilator support. Randomisation Randomization will be done by someone not associated with the care or assessment of the patients by means of a computer generated random number table using an allocation ratio of 1:1:1. Blinding (masking) This is an open level study; neither the physician nor the patients will be blinded. However, the primary and secondary outcome (oxygen saturations, PaO2/FiO2, BP, day specific laboratory tests) will be recorded using an objective automated method; the study staff will not be able to influence the recording of these data. Number to be randomised (sample size) No similar study has been performed previously. Therefore no data are available that could be used to generate a sample size calculation. This phase II study is required to provide some initial data on efficacy and safety that will allow design of a larger study. The trial will recruit 60 participants (20 in each arm). Trial Status Protocol version 1.4 dated May 5, 2020 and amended version 1.5, dated June 16, 2020. First case was recruited on May 27, 2020. By August 10, 2020, the trial had recruited one-third (21 out of 60) of the participants. The recruitment is expected to finish by October 31, 2020. Trial registration Clinicaltrials.gov ID: NCT04403477. Registered 26 May, 2020 Full Protocol The full protocol is attached as an additional file, accessible from the Trial’s 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.

Convalescent plasma associates with reduced mortality and improved clinical trajectory in patients hospitalized with COVID-19

“…Convalescent plasma (CP) from patients who recover from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been in use since the inception of the pandemic to treat Coronavirus Disease 2019 (COVID- 19) (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Discrepant reports of the efficacy of treatments for COVID-19, including CP, emerged from a rapidly evolving political and interventional landscape of the pandemic.…”

Convalescent Plasma for Pregnant Women with COVID-19: A Systematic Literature Review

“…The searches of clinical trial registries for eligible studies under way or planned to investigate the use of CP for COVID-19 during pregnancy were negative. The three protocols for a randomized controlled trial we found during our online search of databases [ 28 , 29 , 30 ] excluded pregnant women from the design.…”

Intravenous Immunoglobulins at the Crossroad of Autoimmunity and Viral Infections

“…Recent results from studies on a large population of critically ill patients show that CP is potentially effective and sufficiently safe in hospitalized patients with COVID-19. Several clinical trials are ongoing to assess safety, efficacy, appropriate effective dose, and dose-response of CP transfusion in COVID-19 patients and to specifically define clinical and laboratory improvements after CP [ 125 , 126 , 127 , 128 , 129 ]. However, no definitive demonstration of a beneficial effect is available, as recently reported [ 119 ].…”