Oral antiviral clevudine compared with placebo in Korean COVID-19 patients with moderate severity
Joon-Young Song, Yeon-Sook Kim, Joong-Sik Eom, Jin-Yong Kim, Jin-Soo Lee, Jacob Lee, Won-Suk Choi, Jung-Yeon Heo, Jang-Wook Sohn, Ki-Deok Lee, Donghui Cho, Ilyoung Cho, Woo-Joo Kim
doi:10.1101/2021.12.09.21267566
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 largescale 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.
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DOI record:
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"abstract": "<jats:p>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.\nMethods: 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.\nResults: 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. \nConclusions: 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.</jats:p>",
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