\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[english]{babel}



\usepackage{float}








\begin{document}

\title{Efficacy and safety evaluation of Azvudine in the treatment of COVID-19
based on four phase III clinical trials.}



\author[1]{Ke-Wei Zhu}%
\affil[1]{Guangzhou Baiyunshan Pharmaceutical Holdings Co Ltd}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Azvudine was included into the Guidelines for the Diagnosis and
Treatment of Coronavirus Disease 2019 (version ninth) issued by the
National Health Commission and National Administration of Traditional
Chinese Medicine announced on August 9, 2022. Numerous domestic public
hospitals introduced Azvudine to copy with the current omicron wave of
the COVID-19 pandemic by the end of 2022. In the study, we
comprehensively evaluated the efficacy and safety of Azvudine using the
clinical data from four phase III clinical trials.%
\end{abstract}%



\sloppy


\textbf{Efficacy and safety evaluation of Azvudine in the treatment of
COVID-19 based on four phase} \textbf{III clinical trials.}

\textbf{Running title:} Efficacy and safety of Azvudine.

\par\null

Ke-Wei Zhu\textsuperscript{1,2}.

\textsuperscript{1}Office of Pharmacovigilance, Guangzhou Baiyunshan
Pharmaceutical Holding Co., Ltd. Baiyunshan Pharmaceutical General
Factory, No. 88, Yunxiang Road, Tonghe Street Baiyun District, 510515
Guangzhou, Guangdong province, China.

\textsuperscript{2}Department of Clinical Pharmacology, Xiangya
Hospital, Central South University, No.110 Xiangya Road, 410008
Changsha, Hunan, China.

\textbf{Correspondence:} Ke-Wei Zhu; fax number: 020-87095309; telephone
number: 020-87095382; email address: zhukew2018@outlook.com; Office of
Pharmacovigilance, Guangzhou Baiyunshan Pharmaceutical Holding Co., Ltd.
Baiyunshan Pharmaceutical General Factory, No. 88, Yunxiang Road, Tonghe
Street Baiyun District, 510515 Guangzhou, Guangdong province, China.

\textbf{Abstract}

Azvudine was included into the Guidelines for the Diagnosis and
Treatment of Coronavirus Disease 2019 (version ninth) issued by the
National Health Commission and National Administration of Traditional
Chinese Medicine announced on August 9, 2022. Numerous domestic public
hospitals introduced Azvudine to copy with the current omicron wave of
the COVID-19 pandemic by the end of 2022. In the study, we
comprehensively evaluated the efficacy and safety of Azvudine using the
clinical data from four phase III clinical trials.

\textbf{Keywords:} Azvudine; efficacy; safety; COVID-19; phase III
clinical trial.

To the editor:

Azvudine as a synthetic nucleoside analog was used to treat adult
patients with plasma HIV-1 RNA more than 100,000 copies/ml through
combination of another nucleoside reverse transcriptase inhibitor (NRTI)
or non-nucleoside reverse transcriptase inhibitor (NNRTI). Azvudine
inhibits RNA-dependent RNA polymerase (RdRp) after phosphorylation,
leading to discontinuation of DNA chain synthesis in
viruses.\textsuperscript{1} Azvudine (Henan Sincere Biotechnology Co.,
Ltd., Pingdingshan, Henan Province, China) was approved by the National
Medical Products Administration (NMPA, Beijing, China) for the treatment
adult HIV-1-infected patients on July 21, 2021. Moderate coronavirus
disease 2019 (COVID-19) was added into the indications of Azvudine to
resist the COVID-19 omicron wave, and this application was conditionally
approved by NMPA on July 25, 2022. The National Health Commission and
National Administration of Traditional Chinese Medicine announced on
August 9, 2022 that Azvudine was included into the Guidelines for the
Diagnosis and Treatment of Coronavirus Disease 2019 (version ninth). The
recommended oral dose of Azvudine for the treatment of moderate COVID-19
is 5 mg once daily, and the duration of Azvudine treatment should not
exceed 14 days.\textsuperscript{2}

By the end of 2022, numerous domestic public hospitals introduced
Azvudine to copy with the current omicron wave of the COVID-19 pandemic.
113 community hospitals admitted Azvudine as a prescription drug in the
treatment of COVID-19 on January 3rd, 2023. However, most of clinician
are unclear about the efficacy and safety of Azvudine. Here, we
comprehensively evaluated it using the clinical data from four phase III
clinical trials.

The three phase III clinical trials were carried out in China, Russia, and
Brazil. In China, the phase III clinical trial was registered in the
Chinese Clinical Trial Registry (ChiCTR2000032769; registration date:
May 9, 2020;
website:\emph{https://www.chictr.org.cn/showproj.aspx?proj=53368} ), and
the clinical trial was simultaneously registered in the International
Clinical Trials Registry Platform (NCT04425772; registration date: May
9,
2020;\emph{https://trialsearch.who.int/Trial2.aspx?TrialID=NCT04425772}).
The randomized, double-blinded, parallel-controlled clinical trial was
carried out in Beijing Ditan Hospital affiliated to Capital Medical
University (Beijing, China) from June 2020 to March 2022. The sponsor
was Henan Sincere Biotechnology Co., Ltd.. A total of 348 COVID-19
patients were enrolled in the study, and the patients were randomly
assigned to the Azvudine group or control group with a 1:1 ratio. The
patients in the Azvudine group received oral Azvudine tablets (5 mg once
daily) plus standard treatment, and the patients in the control group
received Azvudine dummy tablets (placebo) and standard treatment. The
duration of treatment in both the two groups was less than 14 days. The
primary efficacy outcome was the change (reduction) in viral load from
baseline on day 7 and 14. Among the patients with viral load [?] 3log10
copies/ml, the reduction in viral load from baseline on day 3, 5, and 7
in the Azvudine group was higher than that in the placebo group.
However, only the difference in the reduction in viral load from
baseline on day 5 between the Azvudine group and placebo group was
statistically significant (Figure 1). The result was similar to that in
the patients with viral load [?] 4log10 copies/ml. In addition, 341
subjects were involved in safety analysis. 62 subjects experienced 119
adverse events (AEs) in the Azvudine group, while 76 subjects
experienced 175 AEs in the placebo group. Most of AEs were evaluated as
grade 1 or grade 2 according to the Common Terminology Criteria for
Adverse Events (CTCAE) version 4.03 of the National Cancer Institute.
One patient experienced an AE evaluated as grade 3 in the Azvudine
group, and 3 AEs evaluated as grade 3. No AE evaluated as grade 4 or
serious AE occurred. There was no significant difference in the
incidence or severity of AE between the Azvudine group and placebo
group.\textsuperscript{3}

In Russia, the phase III clinical trial was approved by the Russian
Ministry of Health (\emph{http://www.minzdravsoc.ru}) in January 2021,
and was initiated in June 2021. The results of the two phase III clinical
trial performed in China and Russia were disclosed in detail by Fujie
Zhang on the 17th National Infectious Diseases Conference, which was
hosted by the Chinese Medical Association in Anhui,
China.\textsuperscript{3} Fujie Zhang, as a chief physician in the
Beijing Ditan Hospital affiliated to Capital Medical University, was
also the principal investigator (PI) in the Chinese phase III clinical
trial. In addition, the results of the phase III clinical trial performed
in Russia were recorded into the package insert of Azvudine manufactured
by Henan Sincere Biotechnology Co., Ltd. using Chinese language. A total
of 314 patients with moderate COVID-19 were enrolled as the full
analysis set (FAS) in the study, and the patients were randomly assigned
to the Azvudine group or control group with a 1:1 ratio. The primary
efficacy outcome was the median time to improvement in clinical
condition and the proportion of improvement in clinical condition on day
7. 279 patients were eligible according to inclusion and exclusion
criteria, and were included into the per protocol set (PPS), which
consisted of 141 subjects in the Azvudine group and 138 subjects in the
control group. The mean baseline age was 48 years. 39\% and 61\% of
subjects aged 18 \textasciitilde{} 45 years and 45 \textasciitilde{} 65
years (including 45 years), respectively. Male subjects and female
subjects accounted for 43\% and 57\%, respectively. There was no
significant difference in the demographic or clinical characteristics
between the Azvudine group and control group. As shown in Table 1,
Azvudine significantly elevated the proportion of improvement in
clinical condition and reduced the median time to improvement in
clinical condition compared to placebo in both FAS and PPS. With regard
to the safety, 62 patients underwent 119 AEs in the Azvudine group, and
76 patients underwent 175 AEs in the placebo group. Most of the AEs were
determined as grade 1 or grade 2 according to CTCAE version 4.03. Only
one serious AE occurred in the placebo group, and no serious AE occurred
in the Azvudine group. There was no statistically significant difference
in the frequency or severity of AEs between the Azvudine group and
placebo group.\textsuperscript{3}

In Brazil, two phase III clinical trials for Azvudine were registered in
the International Clinical Trials Registry Platform (NCT05033145 and
NCT04668235). Of which, one was performed in patients with mild
COVID-19, and the other one was performed in patients with moderate
COVID-19. The results were detailedly disclosed in the preprints
published on the Research Square platform
(\emph{https://www.researchsquare.com}), and showed that Azvudine
significantly reduced the time of nucleic acid negative conversion
(NANC) as well as the viral load of the patients compared to
placebo.\textsuperscript{4,5}

Taken together, Azvudine could decrease the time of NANC, viral load,
and median time to improvement in clinical condition, and increase the
proportion of improvement in clinical condition on day 7 in the patients
with COVID-19. In addition, Azvudine exhibited good safety and well
tolerance as compared to placebo. In summary, Azvudine was effective and
well-tolerated in the treatment of mild and moderate COVID-1.

\textbf{References}

1. Package insert of Azifudine tablets. In: Henan Sincere Biotechnology
Co., Ltd.; Updated July 28, 2022.

2. Guidelines for the Diagnosis and Treatment of Coronavirus Disease
2019 (version ninth). In: National Health Commission the People's
Republic of China, National Administration of Traditional Chinese
Medicine; 2022.

3. Zhang F. Clinical study of Azfudine against COVID-19. Paper presented
at: The 17th National Infectious Diseases Conference2022; Anhui, China.

4. Cabral P, de Souza S, Silva Rd, et al. Serial Viral Load Analysis by
Ddpcr to Evaluate Fnc Efficacy and Safety in the Treatment of Moderate
Cases of Covid-19.
2022;\emph{https://doi.org/10.21203/rs.3.rs-2273657/v1}. Accessed 21
Nov, 2022.

5. Cabral P, Silva Rd, de Souza S, et al. Serial Viral Load Analysis by
Ddpcr to Evaluate Fnc Efficacy and Safety in the Treatment of Mild Cases
of Covid-19. 2022;\emph{https://doi.org/10.21203/rs.3.rs-2273694/v1}.
Accessed 21 Nov, 2022.

\textbf{Abbreviations}

NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside
reverse transcriptase inhibitor; NMPA, National Medical Products
Administration; RdRp, RNA-dependent RNA polymerase; COVID-19,
coronavirus disease 2019; AE, adverse events; CTCAE, Common Terminology
Criteria for Adverse Events; PI, principal investigator; FAS, full
analysis set; PPS, per protocol set; NANC, nucleic acid negative
conversion.

\textbf{Statements}

\textbf{Ethics approval statement}

NA.

\textbf{Patient consent statement}

NA.

\textbf{Permission to reproduce material from other sources}

NA.

\textbf{Data availabilitystatement}

The datasets used and/or analysed during the current study are available
from the corresponding author on reasonable request.

\textbf{Conflict of interest disclosure}

The authors declare that they have no competing interests.

\textbf{Funding statement}

This report received no funding from any agency in the public,
commercial or not-for-profit sectors.

\textbf{Authors' contributions}

NA.

\textbf{Acknowledgements}

The authors thank all the researchers conducting the four phase III
clinical trials for disclosing and sharing the results to the public.

\textbf{Table 1. The median time to improvement in clinical condition
and the proportion of improvement in clinical condition on day 7 after
administration of Azvudine and placebo.}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
Parameters & Full analysis set & Full analysis set & Per protocol set &
Per protocol set\tabularnewline
\midrule
\endhead
& Azvudine & Placebo & Azvudine & Placebo\tabularnewline
N (missing) & 157 (0) & 157 (0) & 141 (0) & 138 (0)\tabularnewline
Endpoint (\%) & 138 (87.90) & 136 (86.62\%) & 137 (97.16\%) & 136
(98.55\%)\tabularnewline
Censoring (\%) & 19 (12.10) & 21 (13.38\%) & 4 (2.84\%) & 2
(1.45\%)\tabularnewline
Improvement & 57 (36.31\%) & 15 (9.55\%) & 57 (40.43\%) & 15
(10.87\%)\tabularnewline
No Improvement & 100 (63.69\%) & 142 (90.45\%) & 84 (59.57\%) & 123
(89.13\%)\tabularnewline
P value & \textless{} 0.001 & \textless{} 0.001 & \textless{} 0.001 &
\textless{} 0.001\tabularnewline
Mean time & 10.00 & 13.00 & 10.00 & 13.00\tabularnewline
P value & \textless{} 0.001 & \textless{} 0.001 & \textless{} 0.001 &
\textless{} 0.001\tabularnewline
\bottomrule
\end{longtable}

Note:

1. The clinical data were obtained from the package insert of Azvudine
manufactured by Henan Sincere Biotechnology Co., Ltd..

2. The missing values in the primary efficacy outcome was imputed using
a worst value method.

3. Clinical condition was determined according to the WHO Ordinary
Clinical Progression Scale (Jun/2020), Score 4 to 10. The data was
acquired according to the WHO score between day 1 and day 31.

4. The time to improvement in clinical condition was calculated in terms
of the first time improvement in clinical condition emerged, which was
determined by a decrease of [?] 2 in the WHO score. The patients without
any improvement in clinical condition by the end of the study were
denoted as censoring patients. The last time that the WHO scare was
determined was used to calculate the censoring time.

\textbf{Figure legends}

\textbf{Figure 1.} \textbf{The change (reduction) in viral load from
baseline on day 3 and day 5 in patients with mild to moderate COVID-19
treated with Azvudine or placebo.} (A) Patients with viral load [?] 3log10
copies/ml. (B) Patients with viral load [?] 4log10 copies/ml. The P values
indicated the differences in the change (reduction) in viral load from
baseline on day 5 between the Azvudine group and placebo group.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

