key: cord-0334946-dzqk4fn6
authors: Kakinoki, Y.; Yamada, K.; Tanino, Y.; Suzuki, K.; Ichikawa, T.; Nakamura, A.; Kukita, S.; Uehara, A.; Saito, S.; Kuroda, S.; Sakagami, H.; Nagashima, Y.; Takahashi, K.; Suzuki, S.
title: Impact of Antibody Cocktail Therapy Combined with Casirivimab and Imdevimab on Clinical Outcome for Covid-19 patients in A Real-Life Setting: A Single Institute Analysis
date: 2021-10-12
journal: nan
DOI: 10.1101/2021.10.10.21264589
sha: 627683bd5c1b1d479f0a0cd89d6c920bf23e547a
doc_id: 334946
cord_uid: dzqk4fn6

ABSTRACT Background. Recent data from clinical trial suggest that antibody cocktail therapy, a combination of the monoclonal antibodies casirivimab and imdevimab, has been shown to rapidly reduce the viral load and markedly decrease the risk of hospitalization or death among high-risk patients with coronavirus disease 2019 (Covid-19). However, it remains unclear how effective in a real-life clinical setting the therapy is. Methods. We retrospectively analyzed mild to moderate Covid-19 patients with one or more high-risk factors for severe disease who consecutively underwent the antibody cocktail therapy of the disease in our institute in June 2021 through early September 2021, compared to those with high-risk factors who were isolated in non-medical facilities consecutively during the same period, thereby being not given the antibody cocktail therapy there. The key outcome was the percentage of patients with Covid-19-related deterioration which needed additional medical interventions, such as oxygen support or other antiviral therapies. Results. Data from 55 patients with initially receiving antibody cocktail therapy and 53 patients with isolation into non-medical facilities are analyzed. 22 (41.5 %) of 53 patients with isolation facilities were finally hospitalized to receive medical interventions. On the other hand, 13 (23.6 %) of 55 patients with antibody cocktail therapy in our hospital subsequently underwent further medical interventions because of the progression. In multivariate analysis with variables of age, BMI, and high-risk factors, the antibody cocktail therapy significantly reduced 70 % in the need for further medical interventions compared to the initial isolation in the non-medical facilities (odds ratio=0.30, 95%CI [0.10-0.87], p=0.027). Furthermore, patients with 96% or above of SPO2 were significantly more favorable for the therapy than those with 95% or below of SPO2. Conclusion. The treatment of antibody cocktail was closely linked to reduction in the need for further medical interventions. The result indicates that the antibody cocktail therapy is associated with reducing the strain on hospitals, which is related to the improvement of medical management for public health care in Covid-19 pandemic era.

need for further medical interventions. The result indicates that the antibody cocktail 51 therapy is associated with reducing the strain on hospitals, which is related to the 52 improvement of medical management for public health care in Covid-19 pandemic era. REGN-COV2067 trial [6] in high-risk non-hospitalized Covid-19 patients, which showed 70 that the cocktail therapy reduced hospitalization or any-caused death by 70% and Covid-71

19-related symptom duration by 4 days as well as a phase 1 clinical study with safety, 72 tolerability and pharmacokinetics in Japanese people [7] . In addition, the ability of the 73 cocktail to retain activity against emerging variants including delta variant has been 74 demonstrated in vitro study [8] [9] [10] . However, these results have been coming up from 75 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in Hospital which oversaw the study conduct and documentation, and the data available 89 from non-medical facilities were authorized to be provided with fully anonymous 90 condition by the chief officer of the local public health center. This study was conducted 91 in accordance with the principles of the Declaration of Helsinki. 92

Patients assigned to our institute were firstly reviewed to be applicable for the use of and wait situation to see if they progress to the point they need hospitalization (watchful 100 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted October 12, 2021. ; https://doi.org/10.1101/2021.10.10.21264589 doi: medRxiv preprint observation group). When patients possibly progress or got progressed, they were 101 immediately transferred to hospitals to receive some treatments for Covid-19. 102

Key outcomes were designated to the difference between ronapreve and watchful 104 observation groups in terms of the necessity of additional further treatment such as 105 oxygen support or antiviral drugs. In ronapreve group, the addition of further treatment 106 after ronapreve administration indicated the failure of the cocktail therapy as a 107 definition. In watchful observation group, the transfer of patients to hospitals to receive 108 some therapies indicated that patients were under intractable or deteriorating 109

conditions. Other outcomes were designated in ronapreve group to investigate the 110 duration of fever and adverse events after ronapreve administration. 111

Logistic regressioin models for multivariate analysis were applied to evaluate the 113 proposed significant factors in terms of the efficacy of ronapreve, using age, BMI, high-114 risk factors, and Percutaneous oxygen saturation (SPO2) as explanatory variables. 115

Receiver Operating Characteristic (ROC) curves were used to determine the cut-off value 116 for SPO2. All p-values were two sided and P-values of 0.05 or less were considered 117 statistically significant. All statistical analyses were performed with EZR version1.50 118 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a 119 graphical user interface for R (The R Foundation for Statistical Computing, Vienna, 120 Austria). More precisely, it is a modified version of R commander designed to add 121 statistical functions frequently used in biostatistics [11] . 122 123

All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted October 12, 2021. ; https://doi.org/10.1101/2021.10.10.21264589 doi: medRxiv preprint Patients were collected consecutively during the period from June 2021 through early 126

September 2021, when the delta variants were widely spreading in our community. As 127 a result, 55 patients were given Ronapreve first in our institute (ronapreve group) and 128 53 patients were initially assigned to non-medical isolation facilities to see the situations 129 watchfully (watchful observation group) (Table 1) . 130

In ronapreve group, the median age was 51 years, 69.1% were male, and median BMI (Figure 2) . Furthermore, in ronapreve group, patients 153 with 96% or above of SPO2, the cutoff value was established by ROC curves, showed 97% 154 reduction significantly on the additional treatment compared to patients with 95% or 155 below of SPO2 (odds ratio=0.03, 95%CI [0.01-0.22], p<0.001) (Figure 3) . 156

Ronapreve was started at a median time of 3 days from the onset (range; 0 -7 days) 158 ( Figure S1 ). Ronapreve treatment was associated with quick relief from Covid-19-159 related fever. Out of 27 in-patients, 14 patients (51.9%) were reduced from fever until 160 the next day, and all 27 patients has achieved afebrile state until 4 days from the 161 administration, though this result came from limited numbers of 27 in-patients because 162 of missing data from other 28 out-patients (Figure 4) . In regard to vaccinated patients 163 enrolled, in 3 with one shot and in 5 with 2 shots, one and 4 patients showed to be related 164 to the fever-down, respectively (Table S2 ). In aspect of adverse events, one patient 165 showed infusion reaction of mild swelling of eyelids and urticaria of upper arms during 166 the drip of ronapreve, resulting in stopping on the way, and 2 patients showed skin 167 eruption around 2-3 hours after the administration (Table S3) . The important point for ronapreve treatment we mentioned above is that the efficacy for 211 patients is diminished under the condition of 95% or below of SPO2. Since low SPO2 or 212 pneumonia is probably associated with cytokine-storm-induced hyper-inflammation 213 caused by SARS-CoV-2, steroid such as dexamethasone will be more effective to suppress 214 the storm rather than ronapreve, because the antibody treatment probably affects the 215 virus itself. 216

In conclusion, ronapreve, also known as REGEN-COV, is thought to be closely linked to 217 reduction in the risk of hospitalization or the need for additional treatment, along with 218 a potential benefit of prompt recovery from Covid-19-related fever. Although our data 219 provided from a daily practice is small-sized and limited, the antibody cocktail therapy 220 in early phase of the disease suggests a promising way to minimize the serious impact 221 of Covid-19 on the public health care system. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in Multivariate analysis for age≧50 years, 1, or 2, or 3 or more high-risk factors, BMI≧30, 324 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in 

A novel coronavirus from patients with pneumonia 251 in China

2． World Health Organization. WHO Director-General's opening remarks at the media 253 briefing on COVID-19 -11

general/speeches/detail/who-director-general-s-opening-remarks-at-the-mrdia-255 briefing-on-covid

A new coronavirus associated with human respiratory 257 disease in China

Current status of the novel coronavirus 259 infection and the response of the MHLW

5． Ministry of Health, Labour and Welfare. Approval for Ronapreve TM (casirivimab and 262 imdevimab) for the treatment of patients with mild to moderate Covid-19

REGEN-COV antibody cocktail 266 Legends for Tables and Figures 300