The comparative effectiveness of COVID-19 monoclonal antibodies: A learning health system randomized clinical trial

doi:10.1016/j.cct.2022.106822

Randomized Controlled Trial

. 2022 Aug:119:106822.

doi: 10.1016/j.cct.2022.106822. Epub 2022 Jun 11.

The comparative effectiveness of COVID-19 monoclonal antibodies: A learning health system randomized clinical trial

Erin K McCreary¹, J Ryan Bariola¹, Tami E Minnier², Richard J Wadas³, Judith A Shovel², Debbie Albin⁴, Oscar C Marroquin⁵, Kevin E Kip⁵, Kevin Collins⁵, Mark Schmidhofer⁶, Mary Kay Wisniewski², David A Nace⁷, Colleen Sullivan⁸, Meredith Axe³, Russell Meyers³, Alexandra Weissman³, William Garrard⁵, Octavia M Peck-Palmer⁹, Alan Wells⁹, Robert D Bart¹⁰, Anne Yang¹¹, Lindsay R Berry¹², Scott Berry¹², Amy M Crawford¹², Anna McGlothlin¹², Tina Khadem¹³, Kelsey Linstrum⁸, Stephanie K Montgomery⁸, Daniel Ricketts¹⁴, Jason N Kennedy¹⁵, Caroline J Pidro¹⁴, Ghady Haidar¹, Graham M Snyder¹, Bryan J McVerry¹⁶, Donald M Yealy³, Derek C Angus¹⁷, Anna Nakayama¹³, Rachel L Zapf², Paula L Kip², Christopher W Seymour¹⁷, David T Huang¹⁸

Affiliations

¹ Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
² Wolff Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
³ Department of Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁴ Supply Chain Management/HC Pharmacy, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁵ Clinical Analytics, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁶ Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁷ Division of Geriatric Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁸ Clinical Research Investigation and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Health System Office of Healthcare Innovation, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁹ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁰ Health Services Division, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹¹ Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹² Berry Consultants, Austin, TX, USA.
¹³ Health System Office of Healthcare Innovation, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
¹⁴ Clinical Research Investigation and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁵ Clinical Research Investigation and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁶ Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁷ Clinical Research Investigation and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Health System Office of Healthcare Innovation, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁸ Department of Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Clinical Research Investigation and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: huangdt@upmc.edu.

PMID: 35697146
PMCID: PMC9187853
DOI: 10.1016/j.cct.2022.106822

Randomized Controlled Trial

The comparative effectiveness of COVID-19 monoclonal antibodies: A learning health system randomized clinical trial

Erin K McCreary et al. Contemp Clin Trials. 2022 Aug.

. 2022 Aug:119:106822.

doi: 10.1016/j.cct.2022.106822. Epub 2022 Jun 11.

Authors

Affiliations

¹ Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
² Wolff Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
³ Department of Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁴ Supply Chain Management/HC Pharmacy, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁵ Clinical Analytics, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁶ Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁷ Division of Geriatric Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁸ Clinical Research Investigation and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Health System Office of Healthcare Innovation, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁹ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁰ Health Services Division, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹¹ Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹² Berry Consultants, Austin, TX, USA.
¹³ Health System Office of Healthcare Innovation, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
¹⁴ Clinical Research Investigation and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁵ Clinical Research Investigation and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁶ Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁷ Clinical Research Investigation and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Health System Office of Healthcare Innovation, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁸ Department of Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Clinical Research Investigation and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: huangdt@upmc.edu.

PMID: 35697146
PMCID: PMC9187853
DOI: 10.1016/j.cct.2022.106822

Abstract

Background: Monoclonal antibodies (mAb) that neutralize SARS-CoV-2 decrease hospitalization and death compared to placebo in patients with mild to moderate COVID-19; however, comparative effectiveness is unknown. We report the comparative effectiveness of bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab.

Methods: A learning health system platform trial in a U.S. health system enrolled patients meeting mAb Emergency Use Authorization criteria. An electronic health record-embedded application linked local mAb inventory to patient encounters and provided random mAb allocation. Primary outcome was hospital-free days to day 28. Primary analysis was a Bayesian model adjusting for treatment location, age, sex, and time. Inferiority was defined as 99% posterior probability of an odds ratio < 1. Equivalence was defined as 95% posterior probability the odds ratio is within a given bound.

Findings: Between March 10 and June 25, 2021, 1935 patients received treatment. Median hospital-free days were 28 (IQR 28, 28) for each mAb. Mortality was 0.8% (1/128), 0.8% (7/885), and 0.7% (6/922) for bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab, respectively. Relative to casirivimab-imdevimab (n = 922), median adjusted odds ratios were 0.58 (95% credible interval [CI] 0.30-1.16) and 0.94 (95% CI 0.72-1.24) for bamlanivimab (n = 128) and bamlanivimab-etesevimab (n = 885), respectively. These odds ratios yielded 91% and 94% probabilities of inferiority of bamlanivimab versus bamlanivimab-etesevimab and casirivimab-imdevimab, and an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab.

Interpretation: Among patients with mild to moderate COVID-19, bamlanivimab-etesevimab or casirivimab-imdevimab treatment resulted in 86% probability of equivalence. No treatment met prespecified criteria for statistical equivalence. Median hospital-free days to day 28 were 28 (IQR 28, 28) for each mAb.

Funding and registration: This work received no external funding. The U.S. government provided the reported mAb. This trial is registered at ClinicalTrials.gov, NCT04790786.

PubMed Disclaimer

Conflict of interest statement

None of the authors have conflicts of interest to report.

Figures

**Fig. 1**
Epidemiology of Monoclonal Antibody Infusions. Panel A shows the number of mAb-infused patients among the EHR screen eligible. Panel B shows the proportion of mAb-infused patients among EHR screen eligible by White or Black race. Hispanic ethnicity, Other, and Unknown race are not shown due to small sample sizes. Panel C shows the number of mAb infusions per 1000 cases prior to March 10, 2021. Panel D shows the number of mAb infusions per 1000 cases after March 10, 2021. Zip codes with <10 COVID-19 cases or those outside of Pennsylvania are not shown. *Interpretive example:* Prior to the trial (*panel A*), mAb infusion was low. In panel B, the proportion of White and Black race infused among EHR-screen eligible patients increased. In the UPMC catchment in Pennsylvania, mAb infusions also increased in amount (darker, *panel C, D*) and in geographic distribution (more zip code areas colored) during OPTIMISE-C19.

**Fig. 2**
CONSORT Diagram. Due to pharmacy logistics, five patients who received bamlanivimab-etesevimab had been randomly assigned to casirivimab-imdevimab, and seven patients who received casirivimab-imdevimab had been randomly assigned to bamlanivimab-etesevimab. All infused patients who received bamlanivimab monotherapy had been randomly assigned to bamlanivimab monotherapy. The FDA mAb policies changed over time, resulting in varying mAb availability and EUA eligibility criteria over time (Table S1 in Supplement, p 1). .

**Fig. 3**
Hospital-Free Days to Day 28. Primary outcome is displayed as horizontally stacked proportions by monoclonal antibody type. Red represents worse values and blue represents better values. The median adjusted odds ratio from the primary analysis, using a Bayesian cumulative logistic model, were 0.58 (95% credible interval, 0.30–1.16) and 0.94 (95% credible interval, 0.72–1.24) for the bamlanivimab and bamlanivimab-etesevimab groups compared with the casirivimab-imdevimab group. These odds ratios yielded 91% and 94% probabilities of inferiority of bamlanivimab versus bamlanivimab-etesevimab and casirivimab-imdevimab respectively, and an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab at the first prespecified bound. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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References

1. Dougan M., Nirula A., Azizad M., et al. Bamlanivimab plus etesevimab in mild or moderate Covid-19. N. Engl. J. Med. July 14 2021;385:1382–1392. doi: 10.1056/NEJMoa2102685. - DOI - PMC - PubMed
1. Weinreich D.M., Sivapalasingam S., Norton T., et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N. Engl. J. Med. January 21 2021;384:238–251. doi: 10.1056/NEJMoa2035002. - DOI - PMC - PubMed
1. Bariola J.R., McCreary E.K., Wadas R.J., et al. Impact of bamlanivimab monoclonal antibody treatment on hospitalization and mortality among nonhospitalized adults with severe acute respiratory syndrome Coronavirus 2 infection. Open Forum Infect Dis. July 2021;8 doi: 10.1093/ofid/ofab254. ofab254. - DOI - PMC - PubMed
1. Chen P., Nirula A., Heller B., et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N. Engl. J. Med. January 21 2021;384:229–237. doi: 10.1056/NEJMoa2029849. - DOI - PMC - PubMed
1. Jiang S., Hillyer C., Du L. Neutralizing antibodies against SARS-CoV-2 and other human coronaviruses. Trends Immunol. May 2020;41:355–359. doi: 10.1016/j.it.2020.03.007. - DOI - PMC - PubMed

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[1] Dougan M., Nirula A., Azizad M., et al. Bamlanivimab plus etesevimab in mild or moderate Covid-19. N. Engl. J. Med. July 14 2021;385:1382–1392. doi: 10.1056/NEJMoa2102685. - DOI - PMC - PubMed

[2] Dougan M., Nirula A., Azizad M., et al. Bamlanivimab plus etesevimab in mild or moderate Covid-19. N. Engl. J. Med. July 14 2021;385:1382–1392. doi: 10.1056/NEJMoa2102685. - DOI - PMC - PubMed

[3] Weinreich D.M., Sivapalasingam S., Norton T., et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N. Engl. J. Med. January 21 2021;384:238–251. doi: 10.1056/NEJMoa2035002. - DOI - PMC - PubMed

[4] Weinreich D.M., Sivapalasingam S., Norton T., et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N. Engl. J. Med. January 21 2021;384:238–251. doi: 10.1056/NEJMoa2035002. - DOI - PMC - PubMed

[5] Bariola J.R., McCreary E.K., Wadas R.J., et al. Impact of bamlanivimab monoclonal antibody treatment on hospitalization and mortality among nonhospitalized adults with severe acute respiratory syndrome Coronavirus 2 infection. Open Forum Infect Dis. July 2021;8 doi: 10.1093/ofid/ofab254. ofab254. - DOI - PMC - PubMed

[6] Bariola J.R., McCreary E.K., Wadas R.J., et al. Impact of bamlanivimab monoclonal antibody treatment on hospitalization and mortality among nonhospitalized adults with severe acute respiratory syndrome Coronavirus 2 infection. Open Forum Infect Dis. July 2021;8 doi: 10.1093/ofid/ofab254. ofab254. - DOI - PMC - PubMed

[7] Chen P., Nirula A., Heller B., et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N. Engl. J. Med. January 21 2021;384:229–237. doi: 10.1056/NEJMoa2029849. - DOI - PMC - PubMed

[8] Chen P., Nirula A., Heller B., et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N. Engl. J. Med. January 21 2021;384:229–237. doi: 10.1056/NEJMoa2029849. - DOI - PMC - PubMed

[9] Jiang S., Hillyer C., Du L. Neutralizing antibodies against SARS-CoV-2 and other human coronaviruses. Trends Immunol. May 2020;41:355–359. doi: 10.1016/j.it.2020.03.007. - DOI - PMC - PubMed

[10] Jiang S., Hillyer C., Du L. Neutralizing antibodies against SARS-CoV-2 and other human coronaviruses. Trends Immunol. May 2020;41:355–359. doi: 10.1016/j.it.2020.03.007. - DOI - PMC - PubMed

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The comparative effectiveness of COVID-19 monoclonal antibodies: A learning health system randomized clinical trial

Affiliations

The comparative effectiveness of COVID-19 monoclonal antibodies: A learning health system randomized clinical trial

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Conflict of interest statement

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