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.
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.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.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: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;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.3
In Russia, the phase Ⅲ clinical trial was approved by the Russian
Ministry of Health
(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.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 ~ 45
years and 45 ~ 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.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
(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.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.