key: cord-0281032-njutw3ji
authors: Song, J.-Y.; Kim, Y.-S.; Eom, J.-S.; Kim, J.-Y.; Lee, J.-S.; Lee, J.; Choi, W.-S.; Heo, J.-Y.; Sohn, J.-W.; Lee, K.-D.; Cho, D.; Cho, I.; Kim, W.-J.
title: Oral antiviral clevudine compared with placebo in Korean COVID-19 patients with moderate severity
date: 2021-12-14
journal: nan
DOI: 10.1101/2021.12.09.21267566
sha: acd09bdde072e8142ed487c4d2eb8563e9790d2e
doc_id: 281032
cord_uid: njutw3ji

Background: Clevudine, an antiviral drug for chronic hepatitis B virus infection, is expected to inhibit the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Therefore, we conducted a prospective, single-blind, proof of concept clinical study to examine the antiviral efficacy and safety of clevudine compared to placebo in Korean corona virus disease 19 (COVID-19) patients with moderate severity. Methods: Adults with confirmed SARS-CoV-2 infection and symptom onset within 7 days were randomized 2:1 to 120 mg clevudine or placebo to receive one of treatments orally once-daily for 14 days. Antiviral efficacy outcomes were the proportion of patients with real-time reverse transcription polymerase chain reaction (RT-PCR) negative result for SARS-CoV-2 infection and cycle threshold (Ct) value changes from baseline. Clinical efficacy outcomes included proportion of patients who showed improvement in lung involvement by imaging tests, proportion of patients with normal body temperature, proportion of patients with normal oxygen saturation, and the changes in C-reactive protein (CRP) from baseline. Safety outcomes included changes in clinical laboratory tests, vital signs measurement, and physical examination from baseline, and incidence of adverse events. Results: The proportion of patients with real-time RT-PCR negative test and Ct value changes showed no significant difference between clevudine group and placebo group. The changes in Ct value from baseline were significantly greater in clevudine group compared to placebo group in patients with hypertension, and patients who underwent randomization during the first 5 and 7 days after the onset of symptoms. All clinical efficacy outcomes had no significant difference between clevudine group and placebo group. Clevudine was well tolerated and there was no significant difference in safety profile between two treatment groups. Conclusions: This is the first clinical study to compare the antiviral efficacy and safety of clevudine to placebo in Korean COVID-19 patients with moderate severity. The study has demonstrated a possible favorable outcome for the reduction of SARS-CoV-2 replication, with acceptable safety profile, when COVID-19 patients were treated with clevudine. Further large-scale clinical studies, preferably with various clinical endpoints and virus titer evaluation, are required to better understand the effectiveness of using clevudine in COVID-19 treatment. Considering recent trend in clinical development for antiviral drugs, we need to design a clinical study aiming for reducing clinical risk of COVID-19 in mild to moderate patients with at least one risk factor for serious illness.

t-test or Wilcoxon's rank sum test. Analyses were performed using SAS Version 9.4 (SAS Institute Inc., Cary NC) and two-sided tests were performed using an alpha of 0.1 for betweentreatment comparisons. Safety analyses were based on the safety population which consisted of all patients who received at least 1 dose of study drug. The number of patients with AEs and adverse drug reactions (ADRs) in each treatment group were summarized using frequency distribution. Test values and change from baseline were summarized descriptively by treatment group for clinical laboratory test results, vital signs, and physical examination.

A total of 61 patients were analyzed as ITT population and safety population of which 41 and 20 patients were randomized in clevudine and placebo group, respectively. The mean age at baseline was 60.02 (±13.44) and 59.50 (±11.69) years in clevudine and placebo group, respectively. The most common clinical symptom of COVID-19 among all patients were fever (90.16%), cough (65.57%), and myalgia (44.26%). A total of 28 patients (45.90%) had hypertension at baseline, of which 19 and 9 patients were randomized in clevudine and placebo group, respectively. Of all patients, 34 and 49 patients were randomized within 5 and 7 days from the symptom onset, respectively. Baseline characteristics of the patients are shown in Table 1 .

We evaluated the proportion of patients with real-time 8, 11, 15, 22, and 29 . 2 patients of ITT population were excluded from the analysis because they had negative result at baseline. There was no significant difference in the proportion of . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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 14, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 patients with negative result between clevudine group and placebo group at every visit (Table   2) .

Changes in Ct values of E, RdRP, and N genes from baseline to Day 4, 8, 11, 15, 22, and 29 were evaluated. Ct values provided by real-time RT-PCR are highly associated with the copy number of viral RNA and viral load, implicating that higher Ct values relate to lower viral loads. 30, 31 Ct values of all genes at baseline were significantly lower in clevudine group compared to placebo group. Considering that lower Ct values are related to a higher amount of target viral sequence, there was an imbalance in viral load between treatment groups.

Clevudine group showed greater change in Ct values of all genes from baseline to all visits (except Day 8) than placebo group, but there was no significant difference between clevudine group and placebo group at every visit (Table 3 and Figure 2 ). We conducted subgroup analysis by hypertension and time from the symptom onset to randomization on change in Ct values of E, RdRP, and N genes from baseline.

In patients with hypertension, the changes in Ct values of E, RdRP, and N genes from baseline to Day 15, 22, and 29 were significantly greater in clevudine group compared to placebo group (Table 4 and 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 14, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 For patients who underwent randomization during the first 5 days after the onset of symptoms and administered clevudine, the change in Ct value of RdRP gene from baseline to Day 29 was significantly greater when compared to placebo (Table 6 and In patients who underwent randomization during the first 7 days after the onset of symptoms and administered clevudine, the changes in Ct value of RdRP and N genes from baseline to Days 11 and 15 were significantly greater compared to placebo ( 

A total of 43 patients had lung involvement at baseline, of which 28 and 15 patients were randomized in clevudine and placebo group, respectively. We evaluated the proportion of patients who showed improvement in lung invasion at Day 29. There was no significant difference in the proportion of patients who showed improvement in lung involvement between clevudine group (82.14%, 23/28) and placebo group (100%, 15/15) at Day 29 (Table 8) .

The proportion of patients with normal body temperature and the proportion of patients with normal oxygen saturation at Day 4, 8, 11, 15, 22 , and 29 were evaluated, but there was . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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 14, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 no significant difference between clevudine group and placebo group at every visit (Table 9, 10).

Changes in CRP from baseline to Day 4, 8, 15, 22, and 29 were evaluated. Clevudine group showed greater decrease in CRP from baseline to all visits than placebo group, but there was no significant difference between clevudine group and placebo group at every visit (Table 11) .

Clevudine and placebo were related with few and low-grade AEs. The incidence of ADRs were 34.15% (14/41) in clevudine group and 30.00% (6/20) in placebo group. There was no significant difference in ADRs occurrence between clevudine group and placebo group (p=0.7461). Five AEs led to discontinuation of clevudine and withdrawal from the study in five patients compared with one AE in one patient for placebo group. Grade 3 or higher AE occurred only in 1.64% (1/61, hypokalaemia) in the clevudine group and it was resolved. There was no serious AE or fatal outcome in this study. There were no marked differences in results of vital signs, physical examination, electrocardiogram, and laboratory tests between the treatment groups over the 29 days.

The current study found that clevudine was well tolerated but had no significant difference in the proportion of patients with negative result and the clinical efficacy outcomes compared . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted December 14, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 to placebo in COVID-19 patients with moderate severity. However, clevudine was related with antiviral efficacy as evidenced by significant Ct value changes from baseline in patients with moderate COVID-19 and hypertension. The mechanism underlying this efficacy remains unclear. Furthermore, it is reported that antihypertensive drugs and glucose-lowering agents might positively influence the clinical outcomes and disease severity of COVID-19 and the degree of impact is different depending on the class of antihypertensive drugs and glucoselowering agents according to observational retrospective studies. 32-34 Considering these points, there is a need to draw a firm conclusion considering the effect of patient's underlying diseases and concomitant medication on this result.

In patients randomized within the first 5 and 7 days after onset of symptoms, the greater change from baseline on Ct values observed in the clevudine group than the placebo group supports the finding that early treatment with clevudine would have an antiviral effect on SARS-CoV-2. Furthermore, more robust antiviral efficacy of clevudine can be expected in consideration of remarkably higher viral load in clevudine group than in placebo group at baseline.

With regard to safety profile, clevudine was well tolerated with no notable significant differences in ADRs or serious AEs between clevudine and placebo. There were no findings on clevudine that were new or not previously known from established safety information in HBV patients.

Based on the results from this study, the clinical use of clevudine in COVID-19 patients is expected to have a favorable outcome by suppressing the infectious virus replication, lowering viral load, and preventing the spread of COVID-19 in early stages of the infection.

. CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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 14, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 This is the first clinical study to compare the antiviral efficacy and safety of clevudine to placebo in Korean COVID-19 patients with moderate severity. The study has demonstrated a possible favorable outcome for the reduction of SARS-CoV-2 replication, with acceptable safety profile, when COVID-19 patients were treated with clevudine. This study further suggested that clevudine can be a favorable treatment option in the clinical practice for patients with moderate COVID-19, especially patients with hypertension. When we designed this study immediately after COVID-19 outbreak, the epidemiological and clinical features of COVID-19 had not been fully understood, therefore, we designed it as an initial therapeutic exploratory study. For this reason, this study had several limitations related to the study design (e.g., single blinded and small patient population, virological assessment as a primary outcome) and an imbalance in viral load at baseline between two treatment groups. Therefore, further large-scale clinical studies, preferably with various clinical endpoints and virus titer evaluation, are required to better understand the effectiveness of using clevudine in COVID-19 treatment. However, it is not simple to show a significant effectiveness of antiviral treatments in COVID-19 patients with mild or moderate severity because most of these patients do recover naturally from COVID-19 without any treatments. 35 Considering this point, we need to design a clinical study aiming for reducing clinical risk of COVID-19 in mild to moderate patients at risk of severe illness when conducting further study.

This work was supported by Bukwang Pharm. Co. Ltd. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 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 14, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 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 14, 2021. ; https://doi.org/10.1101/2021.12.09.21267566 doi: medRxiv preprint 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 14, 2021. ; https://doi.org/10.1101/2021.12.09.21267566 doi: medRxiv preprint 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 14, 2021. ; https://doi.org/10.1101/2021.12.09.21267566 doi: medRxiv preprint 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 14, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 

WHO Director-General's opening remarks at the media briefing on COVID19

Note) *: Two sample t-test, ￥: Wilcoxon's rank sum test, #: Paired t-test, $: Wilcoxon's signed rank test