Emulation of a Target Trial From Observational Data to Compare Effectiveness of Casirivimab/Imdevimab and Bamlanivimab/Etesevimab for Early Treatment of Non-Hospitalized Patients With COVID-19

  1. Valentina Mazzotta
  2. Alessandro Cozzi-Lepri
  3. Francesca Colavita
  4. Simone Lanini
  5. Silvia Rosati
  6. Eleonora Lalle
  7. Ilaria Mastrorosa
  8. Claudia Cimaglia
  9. Alessandra Vergori
  10. Nazario Bevilacqua
  11. Daniele Lapa
  12. Andrea Mariano
  13. Aurora Bettini
  14. Chiara Agrati
  15. Pierluca Piselli
  16. Enrico Girardi
  17. Concetta Castilletti
  18. Anna Rosa Garbuglia
  19. Francesco Vaia
  20. Emanuele Nicastri
  21. Andrea Antinori

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Abstract

Comparative analysis between different monoclonal antibodies (mAbs) against SARS-CoV-2 are lacking. We present an emulation trial from observational data to compare effectiveness of Bamlanivimab/Etesevimab (BAM/ETE) and Casirivimab/Imdevimab (CAS/IMD) in outpatients with early mild-to-moderate COVID-19 in a real-world scenario of variants of concern (VoCs) from Alpha to Delta.

Methods

Allocation to treatment was subject to mAbs availability, and the measured factors were not used to determine which combination to use. Patients were followed through day 30. Viral load was measured by cycle threshold (CT) on D1 (baseline) and D7.

Primary outcome was time to COVID-19-related hospitalization or death from any cause over days 0-30. Weighted pooled logistic regression and marginal structural Cox model by inverse probability weights were used to compare BAM/ETE vs. CAS/IMD. ANCOVA was used to compare mean D7 CT values by intervention. Models were adjusted for calendar month, MASS score and VoCs. We evaluated effect measure modification by VoCs, vaccination, D1 CT levels and enrolment period.

Results

COVID19-related hospitalization or death from any cause occurred in 15 of 237 patients in the BAM/ETE group (6.3%) and in 4 of 196 patients in the CAS/IMD group (2.0%) (relative risk reduction [1 minus the relative risk] 72%; p=0.024). Subset analysis carried no evidence that the effect of the intervention was different across stratification factors. There was no evidence in viral load reduction from baseline through day 7 across the two groups (+0.17, 95% -1.41;+1.74, p=0.83). Among patients who experienced primary outcome, none showed a negative RT-PCR test in nasopharyngeal swab (p=0.009) and 82.4% showed still high viral load (p<0.001) on D7.

Conclusions

In a pre-Omicron epidemiologic scenario, CAS/IMD reduced risk of clinical progression of COVID-19 compared to BAM/ETE. This effect was not associated with a concomitant difference in virological response.

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  1. Version published to 10.3389/fimmu.2022.868020
  2. ScreenIT

    SciScore for 10.1101/2022.02.04.22270143: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: All consecutive adult patient (age>18) who provided a written informed consent were included in study population.
    IRB: The study was approved by AIFA and National Ethics Committee.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    According to the to manufacturer’s instructions, for the two CMIA, Index >1.4 and Binding Antibody Units (BAU)/mL ≥7.1 are considered positive for anti-N and anti-Spike/RBD IgG, respectively.
    anti-N
    suggested: None
    anti-Spike/RBD IgG
    suggested: None
    Software and Algorithms
    SentencesResources
    SARS-COV-2 serology was performed by ELISA detecting anti-SARS-CoV-2 IgG, IgM, and IgA (ENZY-WELL SARS-CoV-2; DIESSE, Diagnostica Senese, Siena, Italy; positive index values ≥1.1), or by two chemiluminescence microparticle assays (CMIA) detecting anti-Nucleoprotein and anti-Spike/RBD IgG (ARCHITECT SARS-CoV-2 IgG, and ARCHITECT SARS-CoV-2 IgG II Quantitative; Abbott Laboratories, Wiesbaden, Germany, respectively).
    Abbott Laboratories
    suggested: None
    Other RT-PCR methods used to verify the presence of SARS-CoV-2 were the Abbott m2000 RealTime System (Abbott Laboratories, Wiesbaden, Germany) and the Cobas® SARS-CoV-2 Test on the fully-automated cobas® 6800 Systems (Roche Diagnostics, Rotkreuz, Switzerland)
    Abbott
    suggested: (Abbott, RRID:SCR_010477)

    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:
    Our analysis has some limitations. First, due to the observational nature of the study conducted in a single COVID health care center and to the lack of a randomized design, confounding bias cannot be ruled out. Further, eligibility criteria changed over time concurrently with the advent of Delta wave and with a wider use of Bamlanivimab/Etesevimab, due to available supplies. However, results were similar after controlling for MASS score in the regression models. Moreover, the lack of an early measure of CT (e.g. at D3) prevented us from investigating viral load as a potential mediator. Finally, the study was conducted before the emergence of Omicron B.1.1.529 VoC, which is going to subvert previous assessment about mAbs treatment as several in vitro studies suggest that both Bamlanivimab/Etesevimab and Casirivimab/Imdevimab did not retain a remarkable activity against Omicron16–30–31–32. Despite this, even today a proportion of illnesses and consequent hospitalizations are still due to the VoCs different from Omicron, and so knowledge of comparative data between available mAbs is still crucial for optimizing treatment in pandemic times.

    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.

    Results from scite Reference Check: We found no unreliable references.

    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 10.1101/2022.02.04.22270143 on medRxiv