key: cord-1039924-t71htwof
authors: McCreary, E. K.; Bariola, J. R.; Wadas, R. J.; Shovel, J. A.; Wisniewski, M. K.; Adam, M.; Albin, D.; Minnier, T. E.; Schmidhofer, M.; Meyers, R.; Marroquin, O. C.; Collins, K.; Garrard, W.; Berrry, L. R.; Berry, S.; Crawford, A. M.; McGlothlin, A.; Linstrum, K.; Nakayama, A.; Montgomery, S. K.; Snyder, G. M.; Yealy, D. M.; Angus, D. C.; Kip, P. L.; Seymour, C. W.; Huang, D. T.; Kip, K. E.
title: Association of subcutaneous or intravenous route of administration of casirivimab and imdevimab monoclonal antibodies with clinical outcomes in COVID-19.
date: 2021-12-01
journal: nan
DOI: 10.1101/2021.11.30.21266756
sha: e10e4d3acdc0db7f1c0d1df733a97dda1ccab2fe
doc_id: 1039924
cord_uid: t71htwof

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 days 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 and 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 and 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.

4 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 (subcutaneousintravenous) for death, ICU admission, and mechanical ventilation were 0.3% or less, although the 95% confidence intervals were wide.

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.

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Discovery and broad-scale implementation of therapies that decrease progression to severe coronavirus disease 2019 (COVID-19) and improve mortality of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are critical for global health.

Casirivimab and imdevimab is a monoclonal antibody (mAb) that decreases hospitalizations and death in outpatients with mild to moderate COVID-19 when used as treatment or post-exposure prophylaxis. 1, 2 It is available under emergency use authorization (EUA) for these indications in the United States (US), United Kingdom (UK), and other global communities. 3, 4 Only intravenous administration was evaluated in randomized, clinical trials for treatment and accordingly, intravenous infusion is strongly recommended per the U.S. Food and Drug Administration (FDA) for this indication. However, the EUA states subcutaneous injection is an alternative route of administration when intravenous infusion is not feasible and would lead to delay in treatment, though efficacy of subcutaneous injection for treatment of SARS-CoV-2 is unknown.

A COVID-19 surge in September 2021, coupled with healthcare worker staffing shortages, resulted in a capacity crisis for outpatient monoclonal antibody infusions at our learning health system. Key stakeholders and clinical leaders determined that continuation of intravenous therapy would delay or prevent treatment for monoclonal antibody referrals, and conversion to subcutaneous injections would add treatment capacity, reduce appointment times, and expand staff available to administer treatment. The purpose of this study was to evaluate whether or not subcutaneous casirivimab and imdevimab is associated with reduced risk-adjusted 28-day clinical outcomes compared to non-treatment with monoclonal antibodies. We also sought to evaluate the similarity of clinical outcomes comparing subcutaneous with intravenous treatment to inform future operations within our learning health system. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted December 1, 2021 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.

For this analysis, the two research questions were (1) whether or not subcutaneous casirivimab and imdevimab treatment is associated with better 28-day clinical outcomes than non-treatment among mAb-eligible patients; and (2) whether or not subcutaneous casirivimab and imdevimab treatment is clinically and statistically similar to intravenous casirivimab and imdevimab treatment. The primary outcome was the 28-day adjusted risk ratio of hospitalization/death for question 1, and the 28-day adjusted risk difference of hospitalization/death for question 2. Secondary outcomes included 28-day adjusted risk . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted December 1, 2021. ; https://doi.org/10.1101/2021.11.30.21266756 doi: medRxiv preprint ratios/differences of hospitalization, death, composite endpoint of ED admission and hospitalization, and rates of adverse events.

For the first research question, nontreated control subjects were selected from nonhospitalized patients > 12 years of age who had a positive SARS-CoV-2 polymerase chain reaction or antigen test within our health system from July 14 to October 26, 2021. These patients, whose symptom status was unknown, had an EUA-eligible risk factor for progression to severe disease and no admission to the emergency department or hospital on the date of their positive SARS-CoV-2 test result (i.e., presumed not to be at imminent risk of hospitalization).

July 14 th , 2021 was chosen as the start date for this analysis as this was the first confirmed date, per national tracking data, that 100% of patients infected with COVID-19 in our system had the Delta variant; Delta remained the only regional variant until the end of the study period. 6, 7 Corresponding treated subjects were patients > 12 years of age treated subcutaneously with casirivimab and imdevimab in an outpatient infusion center or urgent care facility during the same period as nontreated control subjects. Patients receiving mAb in the emergency department were excluded since subcutaneous route of administration was not used in that setting. Both groups required a 28-day follow-up period. For nontreated control subjects, the 28-day outcome ascertainment period started on the day after the SARS-CoV-2 test positive result. For treated subjects, the 28-day outcome ascertainment period started on the day of mAb treatment.

For the second research question, patients treated subcutaneously or intravenously at an outpatient infusion center or urgent care facility on or after July 14, 2021 and with available follow-up period of 28 days were compared. For both groups, the 28-day outcome ascertainment . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted December 1, 2021. ; https://doi.org/10.1101/2021.11.30.21266756 doi: medRxiv preprint period started on the day of treatment. Since not all clinical sites provided subcutaneous mAb treatment, separate study populations were compiled including all mAb treated patients, as well as the subset of mAb treated patients at clinical sites in which both routes of administration were used (i.e., to remove a potential site effect from the larger analysis). For this cohort to simply examine a scheduled change in practice, intravenous route patients were treated from July 15 to September 8, 2021 and subcutaneous route patients were treated from September 9 to September 29, 2021 (i.e., non-overlapping treatment periods).

We used health-related data captured in the electronic health record and ancillary clinical systems, all of which are aggregated and harmonized in a Clinical Data Warehouse (CDW). 8, 9 For infusion sites with complete EMR data in the CDW, we accessed sociodemographic data, medical history, and billing charges for all outpatient and in-hospital encounters with diagnoses and procedures coded based on the International Classification of Diseases, Ninth and Tenth revisions (ICD-9 and ICD-10, respectively). 10, 11 We assessed 28-day mortality by the hospital discharge disposition of "Ceased to Breathe" sourced from the inpatient Medical Record System, as well as deaths after discharge identified with the Death Master File from the Social Security Administration, 2021 National Technical Information Service as an external data source. 12, 13 

Sociodemographic and clinical characteristics were compared between subjects treated subcutaneously and nontreated control subjects by use of student t-tests or Wilcoxon tests for continuous variables (depending on distributional properties) and chi-square tests for categorical . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

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variables. To control for imbalances in patient profiles between the two groups, we selected nontreated control subjects matched to treated subjects by propensity score methodology. 14, 15 Specifically, propensity scores were derived from a logistic regression model fit from a multitude of variables with subcutaneous mAb treatment as the response variable and forward stepwise selection of measured pre-treatment explanatory variables at p <0.15. We included the variables age, gender, and race into the model prior to stepwise selection. We used 1:2 propensity score matching with a maximum propensity score probability difference of 0.01 to construct the matched treated and nontreated groups. We performed non-matched parallel analyses in which outcomes of treated subjects were compared to nontreated subjects using (adjusting for) the propensity score as a covariate, and with inverse probability weighting. Both the matched and non-matched adjusted analyses were conducted using generalized linear models with mAb receipt as the predictor of interest, specifying the binomial distribution and log link. We did not impute missing values for variables used in deriving the propensity scores.

Sociodemographic and clinical characteristics were also compared between subjects treated subcutaneously and intravenously by use of student t-tests or Wilcoxon tests for continuous variables and chi-square tests for categorical variables. Given few between-group patient differences, we used stepwise logistic regression to examine potential confounders, with age, gender, and vaccination status included as covariates in all models. The primary parameter of interest was the adjusted risk difference (subcutaneous -intravenous) in the 28-day rate of hospitalization/death with a boundary of 3% used to define similar clinical outcome. A 3% boundary was decided as a consensus threshold amongst authors as clinically meaningful for the health system population and for capacity management.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 1 All analyses were performed using the SAS System (Cary, NC), version 9.4. Methods and results are reported in accordance with The REporting of studies Conducted using Observational Routinely-Collected health Data (RECORD) statement (eTable 1). 16 

For the first analysis, there were 969 patients treated subcutaneously with casirivimab and imdevimab and 4,353 non-treated, EUA-eligible controls in the unmatched cohort. The propensity score-matched analysis, which required complete covariate data and matching (as defined in methods), compared 652 patients treated subcutaneously with casirivimab and imdevimab to 1,304 non-treated, EUA-eligible controls (Figure 1 ). For the second analysis, 969 patients treated subcutaneously with casirivimab and imdevimab were compared to 1,216 patients treated with the same mAb intravenously, of whom, 721 versus 441 patients were treated at clinical sites in which both routes of administration were used during the study period ( Figure   1 ).

Prior to matching on propensity score (based on covariate data), subcutaneously treated patients (who were selected using a priority system favoring older age and being immunocompromised starting on September 28, 2021) were significantly older and less likely of Black race than nontreated patients ( Table 1 ). In addition, treated patients had a significantly higher prevalence of rheumatoid arthritis, obstructive sleep apnea, hypertension, and smoking history than nontreated patients. This overall higher risk profile of treated patients was also . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted December 1, 2021. ; https://doi.org/10.1101/2021.11.30.21266756 doi: medRxiv preprint reflected in a higher prevalence of statin and beta blocker use than nontreated patients. Importantly, after propensity score matching, treated and nontreated patients were generally similar on variables included in the propensity score model ( Table 1 , upper portion), the distribution of propensity scores (eFigure 1), and variables not included in the model ( Table 1, lower portion).

The matched 28-day rate of hospitalization/death was 3.4% in treated patients compared to 7.8% in nontreated controls ( Table 2 ). The corresponding risk ratio for 28-day hospitalization/death was 0.44 (95% confidence interval: 0.28 to 0.68, p < .001). The lower risk of hospitalization/death in treated patients was most evident in the first 15 days of follow-up (eFigure 2). The 28-day death rate was 0.2% in the treated group vs. 2.2% in the nontreated group (p=.009 from the log-binomial regression model).

In unmatched patients with a propensity score (i.e., covariate data), the crude 28-day rate of hospitalization/death was 3.5% in treated patients compared to 6.6% in nontreated controls (eTable 2). The corresponding risk ratio for hospitalization or death adjusted for the propensity score was 0.44 (95% confidence interval: 0.29 to 0.66, p < .001). Results were relatively consistent with the use of inverse probability weighting. As in the matched analysis, deaths were infrequent with the 28-day death rate being lower in the treated group (0.2%) compared to the nontreated group (2.1%) (adjusted risk ratio = 0.06, 95% confidence interval: 0.01 to 0.41, p=.004).

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The copyright holder for this preprint this version posted December 1, 2021. ; https://doi.org/10.1101/2021.11.30.21266756 doi: medRxiv preprint Patients treated subcutaneously or intravenously had a mean age of 54 years and a mean Charlson Comorbidity Index score of 0.8; the two groups were also generally similar on demographic and presenting clinical characteristics ( Table 3) . This overall similarity in patient profiles was evident among all treated patients as well as the subset of patients treated at clinical sites in which both routes of mAb administration were used. A notable exception was a higher rate of full COVID-19 vaccination in patients treated subcutaneously (55.5%) compared to those treated intravenously (44.1%) in patients from all sites; however, this rate was similar in patients treated within same sites. The median time (IQR) from symptom onset to infusion was 6 (5, 8) in both groups.

For all infused patients, the adjusted risk difference of hospitalization/death comparing subcutaneous and intravenous treated patients was 1.5% (95% confidence interval: -0.5% to 3.5%, p=.14) which was within the clinically predefined similarity boundary of 3%, yet the upper limit of the 95% confidence interval marginally exceeded this boundary ( Table 4) . The corresponding adjusted risk ratio was 1.71 (95% confidence interval: 0.97 to 3.00, p=.06).

Adjusted risk differences of death and ED admission/hospitalization were small (similar) by route of administration. In terms of initial safety, rates of severe adverse reactions comparing subcutaneous to intravenous patients were 0.0% and 0.2%, respectively.

Among patients treated at clinical sites in which both routes of administration were used, the 28-day risk difference (subcutaneous -intravenous) of hospitalization/death was 1.6% (95% confidence interval: -0.4% to 3.7%, p=.12) ( Table 4 ). The corresponding adjusted risk ratio was 2.62 (95% confidence interval: 0.88 to 7.73, p=.08). Adjusted risk differences and risk ratios for death and ED admission/hospitalization were non-significantly lower in the direction favoring subcutaneous treated patients.

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In supplemental analysis to investigate the clinically small (higher) 28-day risk difference of hospitalization/death in patients treated subcutaneously, the 28-day risk differences of ICU admission and mechanical ventilation (i.e., indicators of severity of hospitalization) were very low and similar in patients treated subcutaneously or intravenously (eTable 3). In addition, length of stay was similar by route of administration among hospitalized patients.

Among a matched analysis of 1,956 patients, subcutaneously administered casirivimab and imdevimab was associated with an estimated 56% lower risk of 28-day hospitalization/death compared to no mAb treatment amongst EUA-eligible outpatients. Among 2,185 patients with mild to moderate COVID-19 treated at an outpatient infusion center, the adjusted risk difference of 28-day hospitalization/death comparing subcutaneous and intravenous mAb treatment was 1.5%, below our pre-defined similarity boundary of 3%. However, the upper limit of the 95% confidence interval (3.5%) exceeded the clinical boundary indicating a possible increased risk of hospitalization with subcutaneous mAb administration. On the other hand, there was little to no evidence that subcutaneous administration was associated with a higher risk of death or severe hospitalization (i.e., ICU admission or mechanical ventilation). Collectively, these data suggest that subcutaneous administration of mAb may be a reasonable alternative to intravenous administration for prevention of death and severe hospitalization.

To our knowledge, this report is the largest analysis of outpatients with mild to moderate COVID-19 treated with subcutaneously administered mAb compared to nontreated and intravenously administered mAb. These non-causal data indicate a consistent, significant benefit of mAb therapy in decreasing hospitalizations and deaths for patients with mild to moderate . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 5 COVID-19, regardless of route of administration in a 100% Delta variant landscape. The adjusted risk difference between subcutaneous and intravenous administration for rate of 28-day hospitalization or death was small and not statistically significant, and there was no difference in risk of severity of illness once hospitalized. This evidence is promising as administering intravenous monoclonal antibodies is logistically challenging, and health systems across the globe continue to face critical staffing shortages amidst high SARS-CoV-2 positive patient volumes. Subcutaneous administration of monoclonal antibodies allows for reduced appointment times (due to elimination of need to place a venous access line and need to infuse the medication over a certain number of minutes), which increases treatment capacity. Indeed, is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 6 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 in real-world settings is logistically challenging and the observed time to treatment in this study represents best practices for mAb treatment across an extensive geographical region. Time to treatment windows will be important to consider as novel, oral antiviral medications become available with reduced treatment windows compared to mAb treatment. 18, 19 Conclusions . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted December 1, 2021. ; https://doi.org/10.1101/2021.11.30.21266756 doi: medRxiv preprint Subcutaneously administered casirivimab and imdevimab was associated with an estimated 56% lower risk of hospitalization or death as compared to no monoclonal antibody treatment in at-risk outpatients with mild to moderate COVID-19. The adjusted risk difference of hospitalization or death comparing subcutaneous and intravenous treated patients was 1.5% (95% confidence interval: -0.5% to 3.5%). Moreover, there was no difference in 28-day risk of death, ICU admission, or mechanical ventilation between subcutaneously or intravenously treated patients. Collectively, these results provide preliminary evidence for potential expanded use of subcutaneous mAb treatment, particularly in areas facing treatment capacity and/or staffing shortages.

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The copyright holder for this preprint this version posted December 1, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted December 1, 2021. Abbreviations: SD, standard deviation; COPD, chronic obstructive pulmonary disease; ACE, angiotensinconverting enzyme.

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The copyright holder for this preprint this version posted December 1, 2021. ; https://doi.org/10.1101/2021.11.30.21266756 doi: medRxiv preprint Abbreviations: CI, confidence interval; ED, emergency department.

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The copyright holder for this preprint this version posted December 1, 2021. ;  criteria, and the sources and methods of case ascertainment and control selection. Give the rationale for the choice of cases and controls Cross-sectional study -Give the eligibility criteria, and the sources and methods of selection of participants . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

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