A phase 2 single center open label randomised control trial for convalescent plasma therapy in patients with severe COVID-19

  1. Yogiraj Ray
  2. Shekhar Ranjan Paul
  3. Purbita Bandopadhyay
  4. Ranit D’Rozario
  5. Jafar Sarif
  6. Deblina Raychaudhuri
  7. Debaleena Bhowmik
  8. Abhishake Lahiri
  9. Janani Srinivasa Vasudevan
  10. Ranjeet Maurya
  11. Akshay Kanakan
  12. Sachin Sharma
  13. Manish Kumar
  14. Praveen Singh
  15. Rammohan Roy
  16. Kausik Chaudhury
  17. Rajsekhar Maiti
  18. Saugata Bagchi
  19. Ayan Maiti
  20. Md. Masoom Perwez
  21. Abhinandan Mondal
  22. Avinash Tewari
  23. Samik Mandal
  24. Arpan Roy
  25. Moumita Saha
  26. Durba Biswas
  27. Chikam Maiti
  28. Ritwik Bhaduri
  29. Sayantan Chakraborty
  30. Biswanath Sharma Sarkar
  31. Anima Haldar
  32. Bibhuti Saha
  33. Shantanu Sengupta
  34. Rajesh Pandey
  35. Shilpak Chatterjee
  36. Prasun Bhattacharya
  37. Sandip Paul
  38. Dipyaman Ganguly

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Abstract

A single center open label phase 2 randomised control trial (Clinical Trial Registry of India No. CTRI/2020/05/025209) was done to assess clinical and immunological benefits of passive immunization using convalescent plasma therapy. At the Infectious Diseases and Beleghata General Hospital in Kolkata, India, 80 patients hospitalized with severe COVID-19 disease and fulfilling the inclusion criteria (aged more than 18 years, with either mild ARDS having PaO2/FiO2 200–300 or moderate ARDS having PaO2/FiO2 100–200, not on mechanical ventilation) were recruited and randomized into either standard of care (SOC) arm ( N  = 40) or the convalescent plasma therapy (CPT) arm ( N  = 40). Primary outcomes were all-cause mortality by day 30 of enrolment and immunological correlates of response to therapy if any, for which plasma abundance of a large panel of cytokines was quantitated before and after intervention to assess the effect of CPT on the systemic hyper-inflammation encountered in these patients. The secondary outcomes were recovery from ARDS and time taken to negative viral RNA PCR as well as to report any adverse reaction to plasma therapy. Transfused convalescent plasma was characterized in terms of its neutralizing antibody content as well as proteome. The trial was completed and it was found that primary outcome of all-cause mortality was not significantly different among severe COVID-19 patients with ARDS randomized to two treatment arms (Mantel-Haenszel Hazard Ratio 0.6731, 95% confidence interval 0.3010-1.505, with a P value of 0.3424 on Mantel-Cox Log-rank test). No adverse effect was reported with CPT. In severe COVID-19 patients with mild or moderate ARDS no significant clinical benefit was registered in this clinical trial with convalescent plasma therapy in terms of prespecified outcomes.

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  1. Version published to 10.1038/s41467-022-28064-7
  2. ScreenIT

    SciScore for 10.1101/2020.11.25.20237883: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementConsent: Ethical approval: The randomized control trial (RCT) on passive immunization with convalescent plasma therapy and all associated studies were done with informed consent from the patients according to the recommendations and ethical approval from the Institutional Review Boards of all the concerned institutions, viz.
    IRB: Ethical approval: The randomized control trial (RCT) on passive immunization with convalescent plasma therapy and all associated studies were done with informed consent from the patients according to the recommendations and ethical approval from the Institutional Review Boards of all the concerned institutions, viz.
    RandomizationEthical approval: The randomized control trial (RCT) on passive immunization with convalescent plasma therapy and all associated studies were done with informed consent from the patients according to the recommendations and ethical approval from the Institutional Review Boards of all the concerned institutions, viz.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableThe inclusion criteria for donors were: age > 18 years, males or nulliparous female convalescent volunteers with history of being positive for SARS-CoV2 on RT-PCR, having weight > 55Kg, complete resolution of symptoms at least 28 days prior to donation, and a negative RT-PCR test for SARS-CoV2 before plasma donation.

    Table 2: Resources

    Antibodies
    SentencesResources
    On the screening day, peripheral blood samples were drawn for the following pre-donation tests: blood group (ABO grouping and Rh phenotyping) and antibody screening for clinically significant antibodies (Extended Rh, Kell, Duffy, Kidd, MNS, antibody screen positive donors were excluded), complete blood count including hemoglobin, hematocrit, platelet count, total and differential leucocyte count (Hb > 12.5g/dl, platelet count > 1,50,000 per microliter of blood and TLC within normal limits were included), screening for HIV, HBV and HCV, MP and syphilis by serology and ID-NAT for Hep B and C and HIV1 (all non-reactive donors by both tests were included), total serum protein (donors with total serum protein > 6gm/dl will be accepted, as per Drugs and Cosmetics (Second Amendment) Rules, 2020.
    HIV1
    suggested: None
    Presence of SARS-CoV-2 neutralizing antibodies in the plasma samples results in inhibition of interaction between HRP-RBD and plate-bound human ACE2 protein, and subsequent development of color, assay results are interpreted as inhibition rate of assay reaction.
    human ACE2 protein,
    suggested: None
    The neutralizing antibody content was measured for all convalescent plasma samples as well as for recipients at T1, T2 and T3.
    T3
    suggested: None
    Presence of anti SARS-CoV-2 IgG antibodies in the plasma was measured using the following formula: Ratio = Extinction of the control or patient samples/Extinction of calibrator (Ratio ≥ 1.1 is interpreted as positive).
    anti SARS-CoV-2 IgG
    suggested: None
    Software and Algorithms
    SentencesResources
    Sequencing in sets of 24 barcoded samples was performed on MinION Mk1B platform by ONT.
    MinION
    suggested: (MinION, RRID:SCR_017985)
    Phylogenetic reconstruction: The assembled SARS-CoV-2 genomes were aligned using MUSCLE aligner in default mode using the software UGENE v34 (Edgar, 2004; Okonechnikov et al., 2012).
    MUSCLE
    suggested: (MUSCLE, RRID:SCR_011812)
    Visualization and further editing of the tree was done in FigTree 1.4.4 (Rambaut, 2012).
    FigTree
    suggested: (FigTree, RRID:SCR_008515)
    Visualisation of the network was performed using Cytoscape 3.7.2.
    Cytoscape
    suggested: (Cytoscape, RRID:SCR_003032)
    Statistical analyses: All statistical analyses, as depicted in the results as well in appropriate figure legends, were performed using R and in some cases using Graphpad Prism 8 or STatistica64 (StatSoft).
    Graphpad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    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:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • 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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2020.11.25.20237883 on medRxiv