Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease

Abstract

Convalescent plasma (CP) therapy in COVID-19 disease may improve clinical outcome in severe disease. This pilot study was undertaken to inform feasibility and safety of further definitive studies. This was a prospective, interventional and randomized open label pilot trial in patients with severe COVID-19. Twenty COVID-19 patients received two 200 ml transfusions of convalescent patient CP over 24-h compared with 20 who received standard of care. The primary outcome was the requirement for ventilation (non-invasive or mechanical ventilation). The secondary outcomes were biochemical parameters and mortality at 28 days. The CP group were a higher risk group with higher ferritin levels ( p < 0.05) though respiratory indices did not differ. The primary outcome measure was required in 6 controls and 4 patients on CP (risk ratio 0.67, 95% CI 0.22–2.0, p = 0.72); mean time on ventilation (NIV or MV) did not differ. There were no differences in secondary measures at the end of the study. Two patients died in the control and one patient in the CP arm. There were no significant differences in the primary or secondary outcome measures between CP and standard therapy, although a larger definitive study is needed for confirmation. However, the study did show that CP therapy appears to be safe in hospitalized COVID-19 patients with hypoxia.

Clinical trials registration NCT04356534: 22/04/2020.

SciScore for 10.1101/2020.11.02.20224303: (What is this?)

Please note, not all rigor criteria are appropriate for all manuscripts.

Table 1: Rigor

Institutional Review Board Statement	Consent: All patients gave written informed consent. IRB: This study was approved by the National COVID-19 Research Committee, and the Bahrain Defence Force Hospital Ethics committee and was conducted in accordance with the Declaration of Helsinki and local regulations.
Randomization	This was a prospective, randomized, controlled open label pilot study involving 40 patients with severe COVID-19 disease confirmed by RT-PCR testing9.
Blinding	Patients and clinicians were not blinded to the treatment given.
Power Analysis	not detected.
Sex as a biological variable	The criteria for donors included (1) ability to give informed consent; (2) men or nulliparous women (all women had a pregnancy test except for postmenopausal women); (3) PCR COVID-19 negative from respiratory tract; (4) patients were symptom free; (5) patients above the ages of 21; (6) body weight more than 50kg; (7) met all donor selection criteria employed for routine plasma collection and plasmapheresis procedures at the collection centre.

Table 2: Resources

Antibodies
Sentences	Resources
Approximately 450 ml of whole blood was venesected together with testing for anti-SARS-CoV-2 antibody titres.	anti-SARS-CoV-2 suggested: None
Software and Algorithms
Sentences	Resources
Statistical analysis were performed using the Stata (StataCorp. College Station,	StataCorp suggested: (Stata, RRID:SCR_012763)

Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:

23 The main limitations of this study were that it was pilot whose main purpose was to guide the design of a definitive study of CP therapy, and as a consequence it lacks the statistical power to conduct outcome hypothesis tests. Determination of the optimal antibody titre from the donors should also be undertaken that was not done in this study, as well a measurement of antibody titre in the recipients before and after the infusions. Moreover, the quantification method for the antibody levels could have been improved and using the neutralizing antibody titre would have been more appropriate; however, at the time of the study, an authorized neutralizing antibody titre test was not available. Furthermore, the antibody titres were also not measured for our patients on randomization. This pilot study showed that it is feasible to perform a phase 3 randomized controlled trial on a larger sample size to determine the effect of plasma, using the current protocol. For a definitive study, the following are suggested modifications 1) Including only plasma with high titre antibody, (defined as ≥250)21; 2)Include only recipients with low antibody titre levels; 3)Serial monitoring of PaO2:FiO2 Ratio in patients; 4)Using of “hard” composite outcome of death or severe ARDS denoted by PaO2:FiO2 Ratio <100; 5)Studying safety endpoint regarding thrombosis in patients using plasma. In conclusion, there were no significant differences in the primary or secondary outcome measures between CP and ...

Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

Identifier	Status	Title
NCT04356534	Completed	Convalescent Plasma Trial in COVID -19 Patients

Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

Results from JetFighter: We did not find any issues relating to colormaps.

Results from rtransparent:

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Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
No protocol registration statement was detected.

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Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease

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