key: cord-0857664-6hr0rg5d
authors: Joy, Aneesh Puthiyedath; Augustine, Anitha Theresa; Karattuthodi, Mohammed Salim; Chandrasekher, Dilip; P, Danisha; Panakkal, Linu Mohan; badaruddeen, Shadia; John, Riya Sara; Murali, Sarath; Thomas, Ardhra Rose; Sahla, Fathimath; Ahmed Kv Ahmed Unni, Shahir; Ahmed, Raseel Omar; Parambil, Jaffer Chalil; Joshi, Madhav A.; Haque Kt, Azharul; Irshad K, Mohammed Izudheen
title: The impact of casirivimab-imdevimab antibody cocktail in patients amidst and post COVID 19 treatment: A retro-prospective comparative study in India
date: 2022-01-19
journal: Clin Epidemiol Glob Health
DOI: 10.1016/j.cegh.2022.100967
sha: bfa5da6bf238484de0b479d61c7dbd1192e61957
doc_id: 857664
cord_uid: 6hr0rg5d

BACKGROUND: Monoclonal antibodies have gained attention in developing countries owing to its benefits portrayed by few clinical trials. However, no studies until now have been undergone in India. METHODS: A retro-prospective comparative observational study was conducted in symptomatic COVID19 patients to evaluate the impact of Casirivimab and Imdevimab antibody cocktail in the high-risk population. Through an extensive data retrieval for 6 months, 152 samples were documented and sorted into test (Casirivimab and Imdevimab treated patients, n = 79) and control (Non- Casirivimab and Imdevimab treated individuals, n = 73) subsets. The research had two phases; first, estimation of mechanical ventilation and high flow oxygen requirement and mortality in samples amidst the treatment, and second was the post COVID19 patients' feedback through validated (Cronbach's alpha coefficient = 0.7) questionnaire that evaluated their health and vaccination status, and treatment satisfaction. RESULTS: We noticed lesser requisite for mechanical ventilation (6.3%; p < 0.001), high flow oxygen (5.1%; p < 0.001) and no death during Casirivimab and Imdevimab therapy. Meanwhile, non-vaccinated test groups were not on mechanical ventilation and those fully immunized seldom entailed high flow oxygen (test, 6.3%; control, 41.9%, p < 0.01). On evaluating the post COVID19 status of each patient in the study, 90.1% of the test samples were healthy and 97.2% were satisfied with the treatment than those in control group. CONCLUSIONS: Casirivimab and Imdevimab regimen was clinically beneficial for high risk COVID19 patients than those treated without the antibody cocktail.

The COVID 19 has moved to new variant, omicron that shocked the subsidiary stage of the pandemic 1 . According to the World Health Organization's latest reports, more cases are adding to the history and still counting, claiming the lives of over 5 million peoples around the globe 2 . The US population is on the edge of catastrophic event and so as other countries. Despite the vaccines serving their goal in preventing the COVID19 occurrences, the circumstance demands advanced and potential management approaches that sterilize the pathogen in clusters of infected patients. Monoclonal antibodies have been demonstrated to be safe and effective in treating viral infections thereby preventing complications. Its direct bind would neutralize the antigen and stimulate anti-body mediated phagocytosis 3 .

Casirivimab and Imdevimab are two IgG1 anti-SARS-CoV-2 monoclonal antibodies, given emergency use authorization by the US Food and Drug Administration-Federal Agency (FDA), European Medical Agency (EMA), and Central Drug Standard Control Organization for ceasing the progression of COVID-19. These agents block the virus's entry into the host cells by specifically attaching to the receptor-binding domain of SARS-CoV-2's, spike glycoprotein 4 . The combination is indicated for high-risk individuals who has Chronic Liver, Kidney (estimated glomerular filtration rate < 60ml/min), and, Respiratory Diseases, immunocompromising conditions, Cardiovascular Diseases, Diabetes Mellitus (HbA1c > 10%), Malignancies, and those with body mass index ≥35Kg/m2, age ≥ 65 of years and other indications that deemed fit by the institutional medical board. The approved dose for those above 12 years of age and weighing at least 40 kg is 600mg for each of the drugs. The diluted combination should be administered as a single intravenous infusion over at least 60 minutes or administered subcutaneously. Since there is limited evidence of these combinations in COVID 19, there would certainly be concerns on population differences and more research is awaiting. A randomized two-part double blinded -controlled trial in the USA is the published study on the safety and efficacy of Casirivimab and Imdevimab in COVID19 5 . In India, there hasn't been any study reported in this discipline. Despite that, the combination has gained attention worldwide and are being consumed by larger communities that open up the essentiality of investigating the impact of the drugs in the Indian population 6 . The study's main objectives were to evaluate the impression of Casirivimab and Imdevimab in COVID19 patients and analyze its post COVID19 patient feedback.

A retro-prospective comparative observational study was performed in patients confirmed with SARS CoV2 with the primary objectives to access the impact of Casirivimab and Imdevimab antibody cocktail in the complication risk communities. The study was conducted in a tertiary care referral hospital of Southern India for 6 months (May 2021 to October 2021) upon approval from the institutional Ethics committee stated by letter No. No.KAS:ADMN: IEC:61:21 and complied with the World Medical Association of Helsinki.

The sample size (n) was calculated by using the formula: -

Where, α=significance Level (5%), P=anticipated prevalence (75%), d =precision (10%), and 72 samples would yield results with 95% confidence interval.

All the in-patients and outpatients who consented to participate upon confirmed diagnosis of COVID19 after antigen test or RT-PCR with oxygen saturation at 93% or above in room air were enrolled. Moreover, the samples were with age greater than 18 years and had symptomatic COVID-19 within 10 days of its onset. Meanwhile, pregnant and lactating women were excluded from the study. Based on inclusion and exclusion study specifications, 152 samples were recruited prior to explaining the study process, privacy, and confidentiality, and their written informed consent was documented.

The study was carried out in 2 phases ( Figure In order to facilitate comparison, the samples were sorted and classified into two. The patients with COVID 19 who were on Casirivimab and Imdevimab antibody cocktail were labelled as the test group (n=79) and those confirmed COVID 19 samples who were on other than Casirivimab and Imdevimab treatment as the control group (n=73).

Patient data were collected from their medical records, prescriptions, and telephonic interviews. A validated, well-formulated data retrieval form was designed to document the samples' COVID 19 treatments. The form also constituted provisions for filling up patient demographic particulars such as patient identifier number, age, gender and, date of COVID positive, and admission and duration of hospital stay. The comorbidities, COVID severity category, mechanical ventilation, high flow oxygen requirement (Bilevel Positive Airway Pressure, High flow nasal cannula) and mortality were also noted. Each patient's C-reactive protein (CRP), serum glucose, D-Dimer, and ferritin values during the initiation of COVID19 treatment were documented.

According to the Health and Family Welfare Department Kerala Guideline for COVID19 treatment, patients were categorized into A, B and C based on symptomatology. They are represented in figure 2.

Patients were communicated through telephone after 29 days to evaluate and assess their post-COVID 19 experiences. Whether they responded or not to our call was also documented. A well-prepared questionnaire comprised of 16 closed-ended questions was designed upon consultation with the COVID19 nodal officer and other general medicine physicians of the hospital. Through the survey tool, the patients in both test and control groups were asked about their health status, treatment satisfaction, vaccination status, post-COVID19 difficulties and adverse reactions, and re-hospitalization. COVID19 treatment affordability was also analyzed in this phase. This questionnaire was statistically feasible with Cronbach's alpha coefficient = 0.704, and confirmatory factor analysis of the survey tool is represented in table 1. It took less than 5 minutes to retrieve this information from the patients.

The collected data were summarized by using frequency and percentages. Statistical analysis was performed by using the SPSS software version 26 (IBM SPSS, Chicago, IL, USA). The Likelihood Ratio or Chi-square test and Man Whitney U test were used to compare the difference in proportion. Factor loadings were obtained for analyzing the principal components. A p-value < 0.05 was considered as significant.

The The prime objective of our study was to evaluate the impact of Casirivimab and Imdevimab antibody cocktails on the need for mechanical ventilation and high flow oxygen requirement and mortality rate ( Finally, we noticed two patients in the control group to die during their COVID treatment period and two post-COVID. However, those in the test group had better life expectancy, with none died during treatment.

The observation was statistically significant with p< 0.05 (Likelihood ratio= 5.98).

This retro-prospective study evaluated the exigency of mechanical ventilation and high flow oxygen and the mortality in COVID 19 symptomatic patients on Casirivimab and Imdevimab. Simon et al. reported that COVID19 fatality has been lowered drastically and are far away from its benign phase 7 . This might be implicated by the health authorities' vaccination drive and protective strategies 8 . However, the latest strains are sprouting seasonally, elevating the population's apprehension. However, the World Health Organization stated the variant to be not more transmissible nor more virulent than their congener 9 . Nevertheless, we should focus on current epidemiological particulars confined to COVID19. The uncertainty of the pandemic end had proposed the monoclonal antibody to serve the patients much better in tackling its complications. Mary et al. demanded the launch of more antibody therapies owing to its long half-life and a single dosing regimen, which would impart the required response in many 10 . However, the cost restricted people in developing countries from proceeding without this advanced treatment. In India, most of the older populations are devoid of adequate economic well-being. They are forced to proceed for other COVID 19 treatment that impose prominent adverse drug reactions 11, 12 . This was the prime reason for the limited availability of samples (n=79) on the Casirivimab and Imdevimab treatment group. Moreover, the Ministry of Health, India, recommended half of dose issued by the FDA and EMA (Casirivimab 1200 mg and Imdevimab 1200 mg) 13 . The agents are preferred for mild to moderate COVID 19 outpatients. However, we had larger samples in the in-patient category to provide better care and medical attention to those on the antibody cocktail 10 .

Elevated C-reactive protein and ferritin, the severity indicator of COVID19, were also noticed in our population 14 . Moreover, a systematic review by Zhufeng et al. pointed out the abundance of Hypertension and Diabetes in COVID19, an observation that coincided with our findings 15 . A cohort multi-center study conveyed the prevalence of COVID19 complications such as Bacterial Pneumonia, Coagulopathies, and Respiratory Distresses in the UK population 16 . Our patients also complained of such events following their treatment. Furthermore, those managed with Casirivimab and Imdevimab were also administered with other agents such as Tocilizumab or Remdesivir, also pointed out in a randomized, controlled, open-label platform trail hosted by RECOVER collaborative group et al. 17 . In our study, few samples with antibody cocktail were on Remdesivir therapy and none had Tocilizumab regimen.

Our main study objective was to discuss the clinical concerns of Casirivimab and Imdevimab on COVID19 symptomatic patients. An interim result from the antibody cocktail study underwent by O'Brien et al. stated complete reduction in PCR-positive COVID19 compared to a placebo group. Their test population did not show viral load for greater than a week 5, 18 . However, in our study, there was no difference across the antibody-treated group and the standard group confined to the length of hospital stay and reversion to J o u r n a l P r e -p r o o f COVID negative status (p>0.5). From an ongoing phase 1 to 3 clinical trial, very limited patients administered with the antibody cocktail demanded medical attention within 29 days 19 . Additionally, Ganesh et al. did not observe need for ventilator support for their patients, however, 2.83% of their samples on Casirivimab and Imdevimab were hospitalized, 7.56% had an emergency departmental visit, and very few were directed to intensive care unit 6 . From our study, 6.3% were on mechanical ventilation, and 24% did not require hospitalization during the treatment period and very few were re-admitted later during their post-COVID phase. This was much lesser when considering those patients on standard COVID 19 treatments. On the other hand, Casirivimab and Imdevimab are not recommended for COVID patients with hypoxia 20 . We identified 94.9% of our study population who did not require high flow oxygen. When we examined the mortality rate, there were no death in those treated with the antibody cocktail. This result resembled the findings put forward by Raymund et al. where, out of 708 patients on Casirivimab and Imdevimab, only an individual passed away 4 .

Our study portrayed the majority of samples to be prior immunized. India's government recommends for initiating monoclonal antibody treatment for COVID19 patients who were also vaccinated. However, the patients should detain any vaccine after the regimen for less than 90 days 21, 22 . Mechanical ventilation was no requirement for those who were non-immunized. This may be due to the efficacy of Casirivimab and Imdevimab and the lesser chance for the antibody cocktail to interfere with vaccine-induced immune responses 23 . Moreover, we noticed a lesser requirement of high flow oxygen among fully immunized and on Casirivimab and Imdevimab (p<0.01). A further remark explained by the research conclusion from Shuva et al. is that they identified the lesser need for oxygen among vaccinated patients 24 . In this context, the vaccine might have generated a synergistic impact on the benefits of the antibody cocktail. We know that the monoclonal antibody is warranted for highly risk communities, so it is essential to consider co-morbidities in our discussion 25 . There was no difference in COVID19 patients between co-existing multiple chronic conditions and both mechanical ventilation and high flow oxygen requirement. This observation would be favorable because the clinical improvement or worsening in patients on antibody cocktails are not affected by co-morbidities.

In the future, more sample size and multi-centric study can be considered yielding better results for the investigation. Moreover, changes in the laboratory parameters, especially the inflammatory markers in COVID 19, can be estimated. Overall, the diminished desideratum for mechanical ventilation, high flow oxygen, and no death enhanced the post COVID19 patient satisfaction much was evident among those on Casirivimab and Imdevimab treated group.

The Casirivimab and Imdevimab treated community had lesser requisite for mechanical ventilation, high flow oxygen and there was no death reported. Meanwhile, non-vaccinated patients in test groups were not on mechanical ventilation and those fully immunized seldom entailed high flow oxygen. On evaluating the post COVID19 status of each patient in the study, majority of those on the antibody cocktail were healthy and were quite satisfied with the treatment. Hence, Casirivimab and Imdevimab regimen are beneficial and can be recommended for high risk COVID19 patients. 

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