Association of subcutaneous or intravenous route of administration of casirivimab and imdevimab monoclonal antibodies with clinical outcomes in COVID-19

  1. Erin K. McCreary
  2. J. Ryan Bariola
  3. Richard J. Wadas
  4. Judith A. Shovel
  5. Mary Kay Wisniewski
  6. Michelle Adam
  7. Debbie Albin
  8. Tami Minnier
  9. Mark Schmidhofer
  10. Russell Meyers
  11. Oscar C. Marroquin
  12. Kevin Collins
  13. William Garrard
  14. Lindsay R. Berry
  15. Scott Berry
  16. Amy M. Crawford
  17. Anna McGlothlin
  18. Kelsey Linstrum
  19. Anna Nakayama
  20. Stephanie K. Montgomery
  21. Graham M. Snyder
  22. Donald M. Yealy
  23. Derek C. Angus
  24. Paula L. Kip
  25. Christopher W. Seymour
  26. David T. Huang
  27. Kevin E. Kip

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Abstract

Importance

Monoclonal antibody (mAb) treatment decreases hospitalization and death in outpatients with mild to moderate COVID-19; however, only intravenous administration has been evaluated in randomized clinical trials of treatment. Subcutaneous administration may expand outpatient treatment capacity and qualified staff available to administer treatment, but association with patient outcomes is understudied.

Objective

To evaluate whether or not, i.) subcutaneous casirivimab and imdevimab treatment is associated with reduced 28-day hospitalization/death than non-treatment among mAb-eligible patients, and ii.) subcutaneous casirivimab and imdevimab treatment is clinically and statistically similar to intravenous casirivimab and imdevimab treatment.

Design, Setting, and Participants

Prospective cohort study of outpatients in a learning health system in the United States with mild to moderate COVID-19 symptoms from July 14 to October 26, 2021 who were eligible for mAb treatment under emergency use authorization. A nontreated control group of eligible patients was also selected.

Intervention

Subcutaneous injection or intravenous administration of the combined single dose of casirivimab 600mg and imdevimab 600mg.

Main Outcomes and Measures

The primary outcome was the 28-day adjusted risk ratio or adjusted risk difference for hospitalization or death. Secondary outcomes included 28-day adjusted risk ratios/differences of hospitalization, death, composite endpoint of ED admission and hospitalization, and rates of adverse events.

Results

Among 1,956 matched adults with mild to moderate COVID-19, patients who received casirivimab and imdevimab subcutaneously had a 28-day rate of hospitalization/death of 3.4% (n=652) compared to 7.8% (n=1,304) in nontreated controls [risk ratio 0.44 (95% confidence interval: 0.28 to 0.68, p < .001)]. Among 2,185 patients treated with subcutaneous (n=969) or intravenous (n=1,216) casirivimab and imdevimab, the 28-day rate of hospitalization/death was 2.8% vs. 1.7%, respectively which resulted in an adjusted risk difference of 1.5% (95% confidence interval: -0.5% to 3.5%, p=.14). The 28-day adjusted risk differences (subcutaneous – intravenous) for death, ICU admission, and mechanical ventilation were 0.3% or less, although the 95% confidence intervals were wide.

Conclusions and Relevance

Subcutaneously administered casirivimab-imdevimab is associated with reduced risk-adjusted hospitalization or death amongst outpatients with mild to moderate COVID-19 compared to no treatment and indicates low adjusted risk difference compared to patients treated intravenously.

Key Points

Question

Among outpatients with mild to moderate COVID-19, is subcutaneously administered casirivimab and imdevimab associated with improved risk-adjusted 28-day clinical outcomes compared to non-treatment with monoclonal antibodies, and clinically similar association compared to intravenously administered casirivimab and imdevimab?

Findings

Among 1,956 propensity-matched adults, outpatients who received casirivimab and imdevimab subcutaneously had a 28-day rate of hospitalization or death of 3.4% (n=652) compared to 7.8% (n=1,304) in non-treated controls [risk ratio 0.44 (95% confidence interval: 0.28 to 0.68, p < .001)]. Among 2,185 outpatients who received subcutaneous (n=969) or intravenous (n=1,216) casirivimab and imdevimab, the 28-day rate of hospitalization/death was 2.8% vs. 1.7%, respectively, which resulted in an adjusted risk difference of 1.5% (95% confidence interval: -0.5% to 3.5%, p=.14). The 28-day adjusted risk differences comparing subcutaneous to intravenous route for death, ICU admission, and mechanical ventilation were 0.3% or less, although the 95% confidence intervals were wide.

Meaning

Subcutaneously administered casirivimab and imdevimab is associated with reduced hospitalization or death amongst outpatients with mild to moderate COVID-19 compared to no treatment, and has a small, adjusted risk difference compared to patients treated intravenously.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2021.11.30.21266756: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: (Project ID 3629) and University of Pittsburgh Institutional Review Board (STUDY21100151)
    Sex as a biological variableStarting on September 28, 2021, patients aged 65 years or older with loss of two or more activities of daily living, pregnant patients, and/or patients with immunocompromised conditions were given priority for mAb treatment appointment scheduling.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    This was a prospective cohort study of patients within the OPtimizing Treatment and Impact of Monoclonal antIbodieS Through Evaluation for COVID-19 embedded learning platform (OPTIMISE-C19, NCT04790786).
    NCT04790786
    suggested: None
    Software and Algorithms
    SentencesResources
    Methods and results are reported in accordance with The REporting of studies Conducted using Observational Routinely-Collected health Data (RECORD) statement (eTable 1).16
    RECORD
    suggested: (RECORD, RRID:SCR_009097)

    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:
    By avoiding limitations associated with intravenous administration, subcutaneous mAb treatment and post-exposure prophylaxis outpatient treatment location sites can potentially reach disadvantaged neighborhoods and low middle-income countries more readily. Our study has limitations. First, nontreated controls were matched by EUA-eligible risk factors only and we were unable to determine symptom severity (whether symptomatic or asymptomatic) in these patients. Thus, many nontreated patients may have been asymptomatic and thereby at low risk of hospitalization, which would tend to bias results against mAb treatment. Second, although adjusted for statistically, more patients in the subcutaneous group were fully vaccinated compared to the intravenous group at all sites, which may also lower risk of hospitalization and death. However, “fully vaccinated” on the referral form meant receipt of two doses of an mRNA vaccine or one dose of an adenovirus vaccine—further details on time from last dose to mAb referral, type of vaccine, or whether or not a third primary series dose had been administered to immunocompromised patients was unknown and therefore fully vaccinated cannot be interpreted as fully protected. This difference was also mitigated when the analysis was restricted to patients treated at same sites. Finally, the mean time from symptom onset to mAb treatment in our study was 6 days. While these therapies work best earliest in disease course, administering treatment faster i...

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

    IdentifierStatusTitle
    NCT04790786RecruitingUPMC OPTIMISE-C19 Trial, a COVID-19 Study

    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.
    • Thank you for including a protocol registration statement.

    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.

  2. Version published to 10.1101/2021.11.30.21266756v1 on medRxiv