key: cord-1001156-e07ynfzj authors: Choi, J.-P.; Kim, H.-J.; Han, J.; Park, S. title: Foistar(Camostat mesylate) associated with the significant decrease in CRP levels compared to Kaletra(Lopinavir/Ritonavir) treatment in Korean mild COVID-19 pneumonic patients. date: 2020-12-15 journal: nan DOI: 10.1101/2020.12.10.20240689 sha: 26ef4c3aa8df65226c3e219c527c3cd5b4081bd2 doc_id: 1001156 cord_uid: e07ynfzj Background There is limited information due to absence of virus titer and symptom related changes. Nonetheless, this is the first comparative study between the use of Foistar (Camostat mesilate) and Kaletra (lopinavir/ritonavir) on COVID-19 infection. Methods Patients with confirmed SARS-CoV-2 infection by positive polymerase chain reaction (PCR) testing that were admitted to Seoul Medical Center (Seoul, South Korea) where is the largest public medical center in South Korea between August 1 and September 20, 2020 were included The data of the patients with pneumonia who received Foistar (Foistar group) during their hospitalization period were primarily collected, and the patients who received Kaletra (Kaletra group) during their hospitalization period were matched to have a similar age group to that of Foistar group so that three times the number of Foistar group patients were randomly selected into Kaletra group and their body temperature, CRP level, WBC count, and event of diarrhea were collected, accordingly. Results A total of 29 patients (7 Foistar group and 22 Kaletra group) was included. The median age was 69, and all had mild COVID-19 (WHO ordinal scale 3 or 4) on admission. 6 patients out of 7 patients (85.71%) from Foistar group who exhibited elevated CRP levels (CRP >0.4mg/dL) on admission have controlled their CRP levels to the normal range. In Kaletra group, 11 out of 18 patients (61.11%) have controlled their CRP levels to the normal range, and only 1 of 2 patients (50.00%) who had normal CRP level has maintained his or her normal CRP level. The difference in the white blood cell counts was not significant between two groups. None of the patients in the study had hyperkalemia. Conclusion This study has found a probable association of controlling inflammatory reactions and fever in COVID-19 patients with Foistar (camostat mesilate) use. In addition, there was no significant adverse drug event found from this study upon the Foistar use. These results may encourage the use of Foistar as a treatment option for the patients with mild to moderate COVID-19. The new coronavirus infection , which began in December of 2019 in Wuhan, China, has spread worldwide. In Korea, the outbreak of patients has surged since February 24, 2020, and finally the World Health Organization (WHO) declared a pandemic on March 14, 2020. COVID-19 has a remarkable propagation power with the high basic reproduction number (R0) of 2-3, and the initial symptoms are non-specific resulting repeated clusters in the community. Currently, there is no effective vaccine or treatment that can suppress the epidemic, so it is very urgent to conduct clinical trials on drugs that can be expected to be effective among drugs developed previously. SARS-CoV-2 is an RNA single-strand virus penetrating into the cells through the endosome by binding to the Spike protein, which is the structural protein, and the angiotensin-converting enzyme 2 (ACE2) receptor on the outer wall of the host inner cell. Type-2 Transmembrane protease (TMPRSS2) promotes priming of S-protein through proteolysis to induce binding to the cell membrane ACE2 receptor.1-3It synthesizes a polypeptide through viral RNA after entering a cell via an endosome. These polypeptides synthesize a RNA polymerase through the formation and activation of a replication-transcriptase complex, and replicate new RNA. The cloned RNA has a lifecycle that generates structural proteins and release them out of the cell again. As described above, the virus penetrates into the cell through the binding of the spike protein and the ACE receptor, and in the meantime, TMPRSS2 plays a role in promoting the priming of the spike protein. 4 Camostat mesilate can be used as an inhibitor of these TMPRSS2 to inhibit cell invasion of the virus. [5] [6] [7] [8] [9] [10] In lined with these assuring mechanisms of action of camostat against COVID-19, a total of 12 clinical trials have been registered in clinicaltrials.gov as of October 2020. [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] The ongoing clinical trials are in the process to confirm the efficacy and safety of camostat in COVID-19 patients in the U.S., the UK, Denmark, Mexico, etc., along with South Korea. Accordinly, Daewoong Pharmaceutical's Foistar Tab., which is composed of camostat mesilate, is expected to be effective in removing virus in COVID-19 patients and helping to relieve their symptoms. Thus, we conduct a retrospective cohort study to confirm the preliminary effectiveness of camostat use in patients with COVID-19 infection. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted December 15, 2020. ; https://doi.org/10.1101/2020.12.10.20240689 doi: medRxiv preprint We retrospectively reviewed medical records of COVID-19 pneumonic patients who confirmed the positive COVID-19 by the RT-PCR test result, and were admitted to Seoul Medical Center between August 1, 2020 and September 20, 2020. We included the patients who were administered with either Foistar (Foistar group) or Kaletra (Kaletra group) within 7 days from admission, and investigated its effectiveness and safety during the hospitalization period. The body temperature, laboratory test results (i.e. CRP level, WBC counts, serum potassium level, etc.), and the number of patients who exhibited one or more events of diarrhea were compared between Foistar group and Kaletra group. Body Temperature: The individual body temperature was recorded on a daily basis during the hospitalization period. Laboratory test results: The records of CRP level, WBC count, serum potassium level of each patient were reviewed. Event of Diarrhea: The number of patients who exhibited an event of diarrhea until discharge. The collected data were analyzed via SAS®(Version 9.4 or above, SAS Institute Inc. NC. USA). The continuous variables (i.e. the number of patients, standard deviations, median, min, max) were presented as descriptive statistics, and the categorical variables were presented as a frequency, or a percentage. The baseline in this study was defined as the day of admission. Any missing data in the day of discharge were replaced by the most current data before the discharge. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted December 15, 2020. ; https://doi.org/10.1101/2020.12.10.20240689 doi: medRxiv preprint A total of 29 patients were analyzed in this study. 7 patients (5 males, and 2 females) were included in Foistar group (camostat), and 22 patients (11 males, and 11 females) were included in Kaletra group (lopinavir/ritonavir 2) Body Temperature The individual body temperature has been recorded on a daily basis and the number of patients who have displayed 38.0 ℃ or above were counted during their hospitalization period. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted December 15, 2020. The patient who became pyretic in Foistar group was administered with camostat one day before the event of fever and required high concentration of oxygen support. The fever was relieved on the following day. ① CRP All seven patients in Foistar group had the elevated CRP levels (>0.4mg/dL) upon admission. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted December 15, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted December 15, 2020. ; https://doi.org/10.1101/2020.12.10.20240689 doi: medRxiv preprint ② WBC Among Foistar group, 5 patients had the normal WBC count (4 -10 x 10 3 /uL), and 2 patients had the abnormal WBC count upon the admission. Among Kaletra group, 17 patients had the normal WBC counts while 3 patients had the abnormal WBC counts and the rest of 2 patients did not proceed the laboratory tests upon the admission. The number of patients who had the abnormal WBC counts upon the admission became normal was 2 in Foistar group, and 1 in Kaletra group. The number of patients who had normal WBC counts upon the admission maintained normal was 5 in Foistar group, and 15 in Kaletra group. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted December 15, 2020. ; https://doi.org/10.1101/2020.12.10.20240689 doi: medRxiv preprint maintained their normal potassium levels. One of the patients (5.00%) who had the normal potassium level upon the admission in Kaletra group has become abnormal. Among the patients who had the abnormal potassium level in the control group, 1 patient (5.00%) has remained abnormal until discharge. An event of diarrhea during the hospitalization period was chart-reviewed. No patient in Foistar group had an event of diarrhea, while 9 patients (40.91%) had one or more events of diarrhea in Kaletra group until the discharge. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted December 15, 2020. ; https://doi.org/10.1101/2020.12.10.20240689 doi: medRxiv preprint Among Foistar group, the event of fever was observed in 1 patient, and none was observed in Kaletra group during the hospitalization period. We have observed a possible advantage of Foistar on the anti-inflammatory effect against COVID-19, given 6 patients out of 7 patients (85.71%) from Foistar group who exhibited elevated CRP levels (CRP >0.4mg/dL) upon the admission have controlled their CRP levels to the normal range. Meanwhile, we concluded that the comparison on fever control, and WBC counts was considered inappropriate due to the significant difference in the baseline between two groups. In addition, we could suggest further safety upon Foistar use as none of the patients have displayed hyperkalemia. a known adverse reaction of Foistar. 25 On the other hand, we observed that the use of Kaletra was likely associated with an event of diarrhea. More than one event of diarrhea was observed from 9 patients out of 22 patients (40.91%) from Kaletra group, while none was found in Foistar group. In conclusion, this study was able to demonstrate a probable association in fever control and the anti-inflammatory effects with the administration of Foistar in COVID-19 patients 26, 27 . Further, the feasible safety profile of Foistar was observed in this study. Thus, the clinical use of Foistar is is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted December 15, 2020. ; https://doi.org/10.1101/2020.12.10.20240689 doi: medRxiv preprint Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity Molecular mechanism of SARS-CoV-2 cell entry inhibition via TMPRSS2 by Camostat and Nafamostat mesylate SARS-CoV-2 differs from SARS-CoV in the requirements for receptor expression and proteolytic activation to trigger cell-cell fusion and is not inhibited by Bromhexine Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity Camostat Mesylate but Not Hydroxychloroquine May Reduce Severity of Organ Failure in COVID-19 Sepsis: A Case-Control Study 20 -). Identifier NCT04470544, Camostat Mesilate Treating Patients With Hospitalized Patients With COVID-19 21 -). Identifier NCT04435015, The Utility of Camostat Mesylate in Patients With COVID-19 Associated Coagulopathy (CAC) and Cardiovascular Complications 19 -). Identifier NCT04353284, Camostat Mesylate in COVID-19 Outpatients 20 -). Identifier NCT04338906, Combination Therapy With Camostat Mesilate + Hydroxychloroquine for COVID-19 20 -). Identifier NCT04524663, Oral Camostat Compared With Standard Supportive Care in Mild-Moderate COVID-19 Patients Identifier NCT04455815, A Trial Looking at the Use of Camostat to Reduce Progression of Symptoms of Coronavirus (COVID-19) in People Who Have Tested Positive But Are Able to Stay at Home 20 -). Identifier NCT04321096, The Impact of Camostat Mesilate on COVID-19 Infection 20 -). Identifier NCT04355052, Open Label Study to Compare Efficacy, Safety and Tolerability of Hydroxychloroquine Combined With Azithromycin Compared to Hydroxychloroquine Combined With Camostat Mesylate and to "no Treatment" in SARS CoV 2 Virus Multiple-dose Study of FOY-305 in Japanese Healthy Adult Male Subjects 20 -). Identifier NCT04530617, Camostat and Artemisia Annua vs Placebo in COVID-19 Outpatients 20 -). Identifier NCT04374019, Novel Agents for Treatment of Highrisk COVID-19 Positive Patients 20 -). Identifier NCT04521296, Efficacy and Safety of DWJ1248 in Patients With Mild to Moderate COVID-19 Compared to the Placebo SARS-CoV-2 Infection of Pluripotent Stem Cell-derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response Camostat Mesilate (package insert). Pharmaceuticals and Medical Devices Agency in Japan Clinical Characteristics of COVID-19: Clinical Dynamics of Mild Severe Acute Respiratory Syndrome Coronavirus 2 Infection Detected by Early Active Surveillance Inflammatory Biomarker Trends Predict Respiratory Decline in COVID-19 Patients