Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial)

  1. Anup Agarwal
  2. Aparna Mukherjee
  3. Gunjan Kumar
  4. Pranab Chatterjee
  5. Tarun Bhatnagar
  6. Pankaj Malhotra

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Abstract

Objective

To investigate the effectiveness of using convalescent plasma to treat moderate coronavirus disease 2019 (covid-19) in adults in India.

Design

Open label, parallel arm, phase II, multicentre, randomised controlled trial.

Setting

39 public and private hospitals across India.

Participants

464 adults (≥18 years) admitted to hospital (screened 22 April to 14 July 2020) with confirmed moderate covid-19 (partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio between 200 mm Hg and 300 mm Hg or a respiratory rate of more than 24/min with oxygen saturation 93% or less on room air): 235 were assigned to convalescent plasma with best standard of care (intervention arm) and 229 to best standard of care only (control arm).

Interventions

Participants in the intervention arm received two doses of 200 mL convalescent plasma, transfused 24 hours apart. The presence and levels of neutralising antibodies were not measured a priori; stored samples were assayed at the end of the study.

Main outcome measure

Composite of progression to severe disease (PaO 2 /FiO 2 <100 mm Hg) or all cause mortality at 28 days post-enrolment.

Results

Progression to severe disease or all cause mortality at 28 days after enrolment occurred in 44 (19%) participants in the intervention arm and 41 (18%) in the control arm (risk difference 0.008 (95% confidence interval −0.062 to 0.078); risk ratio 1.04, 95% confidence interval 0.71 to 1.54).

Conclusion

Convalescent plasma was not associated with a reduction in progression to severe covid-19 or all cause mortality. This trial has high generalisability and approximates convalescent plasma use in real life settings with limited laboratory capacity. A priori measurement of neutralising antibody titres in donors and participants might further clarify the role of convalescent plasma in the management of covid-19.

Trial registration

Clinical Trial Registry of India CTRI/2020/04/024775.

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  1. ScreenIT

    SciScore for 10.1101/2020.09.03.20187252: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: Ethical approval was obtained from the ICMR Central Ethics Committee on Human Research (CECHR-002/2020) as well as from the Institutional Review Boards /Institutional Ethics Committees of all the participating hospitals.
    Consent: All routine screening tests including ABO blood grouping, Rh phenotype, complete blood counts, screening for HIV, HBV, HCV, syphilis, malaria and total serum protein were conducted as per the Drugs and Cosmetics (Second Amendment) Rules, 2020.18 All participants or their family members or legally authorized representatives were provided with information regarding the trial in a language they were comfortable in, and written informed consent was obtained prior to participant recruitment.
    RandomizationStudy Design: The PLACID trial was an open-label, parallel-arm, phase II, multicentre, randomized, controlled trial conducted in 39 tertiary care hospitals across.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablePregnant and lactating women, patients with known hypersensitivity to blood products, recipients of immunoglobulin in the last 30 days, patients with conditions precluding infusion of blood products, participants in any other clinical trials and critically ill patients with PaO2/ FiO2 < 200 or shock (requiring vasopressors to maintain a mean arterial pressure (MAP) > = 65 or MAP < 65) were considered ineligible to participate.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Data were collected in structured paper case record forms (CRF) and then entered in the Research Electronic Data Capture system (REDCap, Version 8.5 Vanderbilt University, Nashville, TN).
    REDCap
    suggested: (REDCap, RRID:SCR_003445)
    Data analysis was done using STATA v14 (College Station, Texas, USA).
    STATA
    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:
    The PLACID trial has several limitations. Being an open-labelled study, it was susceptible to anchoring bias in treating physicians in outcome ascertainment. This may be reflected in the higher resolution of subjective symptoms like shortness of breath and fatigue noted in intervention arm. The trial was conducted in 39 hospitals across the country with some level of heterogeneity across the trial sites in terms of BSC and participant enrolment. The biomarker assays for ferritin, LDH, CRP and D-dimer were conducted with products from different manufacturers. Also, as the pandemic was in different stages across the country, the enrolment strength varied from site to site with a possibility of selection bias arising due to clustering of enrolment. We attempted to alleviate this bias by statistically adjusting the primary outcome for trial sites. Further, the discharge criteria for COVID-19 was based on government guidelines and not on clinician discretion and patient condition, hence we chose not to analyse this as a secondary outcome. We could not measure the antibody titres in CP before transfusion, since validated, reliable, commercial tests for qualitative or quantitative antibody measurement were not available at the time of commencement of this trial. However, this remains a close approximation of the manner in which CP therapy has largely been deployed in regions with limited laboratory capacity. Use of CP as a treatment modality for COVID-19 has received authorisation f...

    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.

  2. Version published to 10.1136/bmj.m3939
  3. Version published to 10.1101/2020.09.03.20187252v2 on medRxiv
  4. Version published to 10.1101/2020.09.03.20187252v1 on medRxiv