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 International Journal of Infectious Diseases 115 (2022) 62–69

Contents lists available at ScienceDirect

International Journal of Infectious Diseases

journal homepage: www.elsevier.com/locate/ijid

Phase III, Randomized, Double-blind, Placebo controlled trial of

Efficacy, Safety and Tolerability of Antiviral drug Umifenovir vs
Standard care of therapy in non-severe COVID-19 patients ✩
Ravishankar Ramachandran 1,∗∗, Vivek Bhosale 1, Himanshu Reddy 2, Virendra Atam 2,
MMA Faridi 3, Jalees Fatima 3, Vaibhav Shukla 3, Zaw A Khan 3, Hana Khan 3, Vikram Singh 4,
Mahendra Pal Singh Negi 1, Mukesh Srivastava 1, Ajay Kumar Srivastava 1,
Chandra Bhushan Tripathi 1, Nayan Ghosh 1, Nilanjana Majumdar 1, Raj Kamal Tripathi 1,
Srikanta Kumar Rath 1, Prabhat Ranjan Mishra 1, Sharad Sharma 1, Tapas K Kundu 1,∗
1
CSIR-Central Drug Research Institute, Lucknow
2
King George’s Medical University, Lucknow
3
ERA’s Lucknow Medical College and Hospital
4
Ram Manohar Lohia Institute of Medical Sciences, Lucknow

a r t i c l e i n f o a b s t r a c t

Article history: Objective: To test efficacy, safety and tolerability of Umifenovir in non-severe COVID-19 adult patients.
Received 21 October 2021 Methods: We carried out randomized, double-blind, placebo-controlled, multicenter, phase III trials in-
Revised 10 November 2021
volving adult (18-75 years), non-severe COVID19 patients, randomized 1:1 on placebo or Umifenovir
Accepted 14 November 2021
(800 mg BID, maximum 14 days) respectively along with standard-of-care. The primary endpoint for
Asymptotic-mild patients was time to nasopharyngeal swab RT-PCR test negativity. For Moderate patients,
the average change in the ordinal scale from the baseline scores on the eight-point WHO ordinal scale
was assessed.
Results: 132 patients were recruited between 3rd October to 28th April 2021, of which 9 discontinued due
to various reasons. In Mild-asymptomatic patients (n=82), we found that 73% patients in the Umifen-
ovir arm were RT-PCR negative, while 40% patients in the placebo arm were negative (P=0.004) on day
5. However, in the moderate group (n=41), the WHO scores for the Umifenovir arm was not statisti-
cally significant (P=0.125 on day 3), while it was statistically significant in the Mild-asymptomatic group
(P=0.019 on day 5).
Conclusion: Umifenovir meets the primary and secondary endpoint criteria and exhibits statistically sig-
nificant efficacy for Mild-asymptomatic patients. It is efficacious, safe and well-tolerated at the tested
dosage of 800mg BID, maximum 14 days.
© 2021 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)

Introduction
The COVID-19 pandemic caused by the Severe Acute Respira-
tory Syndrome Coronavirus-2 (SARS-Cov2) has ravaged almost ev-
✩ ery nation across the globe (World Health Organization, 2021).
This study is registered with the Clinical Trial Registry of India (CTRI) with
Number: CTRI/2020/09/027535. In India alone, over 30 million persons have been infected by
∗
Corresponding authors. Tapas K. Kundu, Director, CSIR-Central Drug Research the virus and about 0.4 million people have been officially de-
Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow-226031, India. clared dead due to the disease and its complications (https://www.
Phone: +91-522-2772450. mygov.in/covid-19). Vaccination strategies are obviously vital to
∗∗
Ravishankar Ramachandran, CSIR-Central Drug Research Institute, Sector 10,
control the pandemic (https://www.who.int/emergencies/diseases/
Jankipuram Extension, Sitapur Road, Lucknow-226031, India. Phone: +91-522-
2772477. novel-coronavirus-2019/covid-19-vaccines/advice) and at the same
E-mail addresses: time it is critical to have evidence-based therapeutics that can mit-
[email protected] (R. Ramachandran), [email protected] (T.K. Kundu).

https://doi.org/10.1016/j.ijid.2021.11.025
1201-9712/© 2021 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
R. Ramachandran, V. Bhosale, H. Reddy et al. International Journal of Infectious Diseases 115 (2022) 62–69

igate the disease that can occur in, both vaccinated, and unvacci- dosage of 800mg achieves sufficient concentration to inhibit the
nated persons. pathogen. The drug has a half-life of about 16 hours and it was
Umifenovir (Arbidol) is known to have broad spectrum anti- therefore decided to be administered twice daily. The standard
viral activity and has earlier been approved in China and Russia care of therapy used was as per the Ministry of Health, Govt. of In-
for treating influenza, SARS, and Lassa viruses (Blaising et al, 2014; dia COVID-19 treatment guidelines (https://www.mohfw.gov.in/pdf/
Cheng & Shan, 2019; Boriskin et al., 2008; Chen et al., 2020; 6. UpdatedDetailedClinicalManagementProtocolforCOVID19adultsdated-
Pécheur E-I et al., 2016). It has been suggested and tested in mul- 24052021.pdf). Patients were randomized using Computerised ran-
tiple studies as a candidate for use as an anti-COVID19 therapeutic domization (Sequentially numbered opaque, sealed envelopes
and has been suggested to act at the entry stage and at the post- –SNOSE).
entry stages by preventing viral attachment and inhibiting the re- The inclusion criteria involved chiefly the following: Asymp-
lease of virus particles from intracellular vesicles respectively (Xi tomatic persons: aged 18-75 years, at the time of signing the In-
Wang et al., 2020, Zheng et al, 2020; Blaising et al., 2013). Earlier formed Consent Form (ICF), with Nasopharyngeal swab positivity
clinical trials have reported mixed results about its efficacy (No- in RT-PCR tests for SARS-Cov-2 antigens detected during screen-
jomi et al., 2020; Darazam et al., 2021; Yethindra et al., 2020; Xu ing of contacts or sentinel surveillance. Mild patients were those
et al., 2020; Deng et al., 2020; Gao et al., 2020; Huang et al., 2020; with uncomplicated upper respiratory tract viral infection and who
Zhu et al., 2020; Lian et al., 2020). The EC50 , 50% maximal effec- may have non-specific symptoms such as fever, cough, expectora-
tive concentration has been reported to be 4.11 μM while the 50% tion, shortness of breath, myalgia, fatigue, sore throat, nasal con-
cytotoxic concentration, CC50 , has been reported to be 31.79 (7,19). gestion, diarrhea, loss of taste with Nasopharyngeal swab positiv-
Our hypothesis, based on the evaluation of multiple in vitro and ity in RT-PCR tests for SARS-Cov-2 antigens. Moderate disease was
clinical studies, was that Umifenovir is a drug with a good safety considered as Pneumonia with no signs of severe disease. Adults
profile (LD50 ∼4g/kg), and with the capacity of achieving the re- with presence of clinical features of dyspnea and or hypoxia, fever,
quired EC50 with a dose of 800mg. Earlier relevant human studies cough, including SpO2 <94% (range 90-94%) on room air, respira-
had identified a Cmax ∼4.1 μM upon administration of 800 mg of tory rate more or equal to 24 per minute were included in the
Umifenovir and a half-life of about 16 hrs. (Sun et al., 2013). On moderate patient category.
the other hand, other reported clinical trials involving Umifenovir The main exclusion criteria were: patients with severe covid
have all used a maximum of 600 mg/day as the dosage. and with respiratory rate >30 breaths/min, severe respiratory dis-
We therefore aimed to evaluate the Efficacy, Safety and Toler- tress, SpO2 <90% on room air, Cases of Acute respiratory distress
ability of Umifenovir vs Standard care of therapy through a ran- syndrome (ARDS), sepsis/ septic shock, pregnant/ lactating women,
domized Phase III double-blinded placebo controlled trial in non- patients with severe lever disease, severe renal impairment, or
severe COVID-19 adult patients in the age group of 18-75 yrs using other comorbidities like asthma, diabetes with second and third
a dosage of 800mg BID administered orally. An entry inhibitor is line medicines as defined in the WHO guidance document (World
expected to have more efficacy in the earlier stages of the COVID19 Health Organization, 2020a). The clinical trial protocol is attached
disease, while moderate/severe disease is supported by other host- as Supplementary information.
directed clinical measures for alleviation of symptoms. Accordingly, Randomization and masking
separate endpoints were devised for Mild-asymptomatic and mod- Patients who were eligible as per the inclusion criteria were
erate patients respectively based on the known disease progress asked to give their consent to participate in the trial. Randomiza-
and nationally adopted standard-of-care treatment strategies. To tion and recruitment was administered by an independent clin-
our knowledge, this report is the first for a double-blind placebo ical trial coordinator for true double-blinding. Patients were al-
controlled Phase III trial for Umifenovir against COVID-19 and fur- most equally stratified into the Mild-asymptomatic and Mod-
thermore no other trial has involved the dosage of 800 mg BID erate arms. All laboratory staff and doctors were also masked
that has been used here. to treatment allocation and samples were identified by serial
Methods numbers.
Study design, randomization, and inclusion/exclusion of partici- Study population and criteria
pants Calculation of sample size for the overall study
A double-blind placebo controlled Phase III trial was designed The patients were assigned to the three hospitals by a Cen-
to be carried out in three clinical trial centres based in Lucknow, tral COVID-19 command center of the State government of Uttar
India, viz. King George’s Medical University, Ram Manohar Lohia Pradesh, India. A total of 132 patients were to be recruited with 66
Institute of Higher Medical Sciences and Era’s Lucknow Medical patients in each arm of the trial. The sample size of the present
College and Hospital for a total of 132 patients. All National reg- study was chosen based on formal statistical power calculation for
ulatory and respective ethical committees’ permissions/ approvals the primary outcome measure i.e. nasopharyngeal swab negativ-
were secured before the commencement of the trial. Patients were ity by RT-PCR test. Sample size estimation was based on assump-
referred to the respective hospitals by a central command center tion that the average time (duration) of discharge of patient in
under the Directorate of Medical & Health Services, State gov- Standard-of-care (SOC) group is 13± 2.5 days. For any patient to
ernment of Uttar Pradesh (http://dgmhup.gov.in/en/default) based be discharged in lesser time than 11.7 days we require the sample
on positive RT-PCR results of persons with symptoms or through size to be calculated as:
contact tracing of already identified COVID-19 positive patients Ƞ = 2(Z α /2 + Z β )2 σ 2 / (x1 - x2)2
(https://lucknow.nic.in/noval- corona- virus- covid- 19/). Dosage of Where Z α /2 = 1.96 level of significance, Z β = 0.842 power of
Umifenovir used in the study was 800mg (2 tablets, 400mg each) test= 80%, x1 = 11.7 days, x2 = 13 days, (x1 - x2) = 1.3, σ = 2.5
administered orally twice daily for 14 days plus standard care of days, x1 - x2 the minimum time difference which can be signifi-
therapy. The adherence in admitted patients was done under direct cant.
observation. For those who were isolated at home, the adherence Ƞ = 2 × (1.96 + 0.842)2 × 2.52 /1.32 = 58
was ensured by pill counting every 3 days. Each patient enrolled With 10% margin of dropouts and also taking into account ran-
in the study gave written consent and was observed for a total domization block size of 6, the required sample size was calculated
of 28 days normally. Case categories according to severity was to be 66 in each arm. Ultimately, 9 patients withdrew from the
defined as per Ministry of Health & Family Welfare, Govt of India trial by not appearing for subsequent tests or stopped taking the
guidelines. As per the earlier reported pharmacokinetic studies, a medication (either Umifenovir/ placebo) leading to a total of 123

63
R. Ramachandran, V. Bhosale, H. Reddy et al. International Journal of Infectious Diseases 115 (2022) 62–69

patients divided into placebo (n=63) and Umifenovir (n=60) arms domization on the eight-point ordinal scale as defined by WHO.
respectively. This would assess the clinical recovery of the patients on both
Outcomes and safety assessments arms of the trial in the Mild-asymptomatic patients. In this anal-
The primary endpoints for the Mild-asymptomatic patients was ysis we found that the WHO score on day 5 was 48.9% lower in
different from Moderate patients. For the Mild-asymptomatic pa- the Umifenovir group (P=0.019) compared to the placebo group
tients, the primary endpoint was Time from randomization to na- (Figure 3, Table 3).
sopharyngeal swab negativity by two RT-PCR tests, for SARS-Cov- Overall, the primary and secondary endpoints are met for the
2 antigens, taken 24 hours apart. For moderate patients, the end Mild-asymptomatic category of patients.
point was time to improvement by one category from randomisa- Calculation of sample size and power of test for Mild-
tion on the eight-category ordinal scale defined by World Health asymptomatic patient category.
Organisation, 2020b (Table S1) & average change in the ordinal We carried out calculations to determine the post hoc power of
scale from baseline. The secondary outcome was Time from ran- the above results.
domization to clinical recovery or deterioration, assessed at 0, 7, Assuming a difference of 20% to be significant between Placebo
14, 21 and 28 days, on the WHO eight-category ordinal scale. Also and Umifenovir arms in the Mild-asymptomatic category and with
assessed was the proportion of patients to clinical recovery or de- α level of significance and with 80% power of the test the sam-
terioration, at 0, 7, 14, 21 and 28 days respectively, on the WHO de- ple size per group is: n = {2∗ (Zα /2 + Zβ )2 ∗ P∗ Q}/2 where; Zα /2
fined eight-category ordinal scale consisting of the following cate- =1.96, Zβ =0.842, P=0.9, Q=0.1 and =0.2.
gories: (a) Proportion of patients hospitalized with Severe Covid-19 This gives n=35.3, i.e n=36.
pneumonia (with respiratory rate ≥30/minute and/or SpO2 < 90% Hence the minimum sample size per group in this study was de-
in room air) or ARDS or Septic shock as per Government of India termined to be n=36.
guidelines. (b) Adverse events in the two groups. [P = Pooled rate of response; Q = 1-P; Zα /2 = Desired level of
Statistical analysis: significance (0.05)
Discrete (categorical) nasopharyngeal swab/RTPCR output (neg- Zβ = Value of Z when power is 80%;  = minimum difference
ative/positive) of two groups (placebo, n=63 and umifenovir, n=60) in rate of response of placebo and treatment group to be signifi-
over the periods (day 5, 7, 9, 11, 13, 15, 17, 19, 21 and 28) were cant].
summarised in number (n) and percentage (%) and compared by Based on this, the post hoc power of the results was estimated
chi-square (χ 2) test. The WHO score of two groups over the pe- to be 84.5%. Since the estimated power is more than the expected
riods (day 3, 5, 7, 14, 21 and 28) were summarised in Mean ± SE power of test, it can be concluded that the sample size stud-
(standard error of the mean) and compared by repeated measures ied is sufficient to justify the significant effect of the Umifenovir
two factor (groups and periods) analysis of variance (ANOVA) and group over the placebo group in the Mild-asymptomatic patients
the significance of mean difference within (intra) and between (in- too.
ter) the groups was done by Newman-Keuls post hoc test. A two- Analysis of trial endpoints for Moderate category patients.
tailed (α =2) P < 0.05 was considered statistically significant. As mentioned earlier, for Moderate patients, the average change
This study is registered with the Clinical Trial Registry of India in the ordinal scale from the baseline scores from randomization
(CTRI) with Number: CTRI/2020/09/027535 and was conducted be- on the eight-point ordinal scale as defined by WHO was calculated
tween 3rd October 2020 – 28th April 2021. as the primary endpoint. The distribution of WHO score, Mean ±
Role of the funding source SE, of the two treatment groups in Moderate patients (n=41) is
The funder had no role in the study design, conduct of the trial given in Figure 4, Table 4.
or the writing of the report We found that in the Moderate patients group the reduction in
Results the mean WHO score was not statistically significant (P=0.125 &
Patients were recruited into the trial and randomized into the 0.281 on days 3 and 5 respectively).
Umifenovir arm + standard of care or Placebo + standard of care Adverse Events (AE)
respectively. They were stratified into Asymptomatic, Mild and We found that Umifenovir was well tolerated. No serious ad-
Moderate categories almost uniformly. Out of 132 patients who verse events were noted in the patients and additionally no deaths
were recruited, 9 withdrew consent or stopped taking medication were seen in any of the groups. A total of 14 patients with mi-
on their own and were discontinued from the trial. The remaining nor adverse events were noted (Table 5) with symptoms ranging
123 patients were found to be divided as placebo group (n=63) from headache, stomach ache, nausea and vomiting. The patients
and Umifenovir group, (n=60) respectively (Figure 1). The base- who exhibited minor AEs were almost equally divided between
line characteristics of recruited participants was assessed and is the Umifenovir and Placebo groups respectively. Further our as-
quite similar in both groups of patients and also within strati- sessment of all patients on 0,7,14,21 and 28 days on eight-category
fied Mild-asymptomatic and moderate patients (Table 1). When we ordinal scale defined by WHO supported no deterioration of the
examined the symptom category of patients, we found that the clinical status. Additionally, the analysis of laboratory parameters
recruited patients were similarly distributed with Asymptomatic also showed that clinically significant changes were not found in
(35%), Mild (32%) and Moderate (33%) respectively. both patient groups. This is as expected, as Umifenovir has been
Primary endpoint analysis for Mild-asymptomatic patients safely used for over 25 years as an over the counter medicine and
As mentioned earlier, the primary endpoint for this category is in line with other reported trials.
of patients was time to RT-PCR nasopharyngeal swab negativity Discussion
by two RT-PCR tests for SARS COV2 antigens taken 24 hrs apart Umifenovir is a safe drug used for over 25 years in Russia and
from the date of randomization. In the Mild-asymptomatic group China against Influenza. It has been approved for use in children
(n=82), we found that: 73% patients on the Umifenovir arm were and pregnant women from the second trimester onwards in these
RT-PCR negative on the 5th day (P=0.004) as compared to only countries. It was used as a standard of care/ trialled in the latter
40% patients on the placebo arm (Figure 2, Table 2). countries in the earlier stages of the COVID19 pandemic and the
Secondary endpoint analysis for the Mild-asymptomatic pa- earlier trials suggested better benefits as compared to drugs like
tients’ category Lopinavir/Ritonavir. However, retrospective studies involving hos-
The secondary endpoint was the average change in the ordinal pitalization or severe cases were not clear in their conclusion and
scale by at least one category from the baseline scores from ran- the reports suggested that additional studies are needed.

64
R. Ramachandran, V. Bhosale, H. Reddy et al. International Journal of Infectious Diseases 115 (2022) 62–69

Figure 1. Patient randomization and distribution shown as a CONSORT diagram. The Umifenovir and placebo groups contained 60 and 63 patients respectively in the analysis.

Table 1
Comparison of baseline demographic characteristics of all recruited patients between two
drug groups. Age, height and weight of two groups were summarised in Mean ± SE and
compared by Student’s t test whereas sex were summarised in number (n) and percentage
(%) and compared by χ 2 test

(A) Overall patients (n=123)

Variable Placebo (n=63) (%) Umifenovir (n=60) (%) t/χ 2 value P value
Age (yrs) 47.35 ± 1.96 46.08 ± 1.93 0.46 0.646
Sex:
Female 19 (30.2) 12 (20.0) 1.68 0.195
Male 44 (69.8) 48 (80.0)
Height (cm) 164.86 ± 0.88 165.60 ± 0.81 0.62 0.537
Weight (kg) 69.51 ± 1.02 69.03 ± 1.09 0.32 0.751
(B) Mild-asymptomatic patients (n=82)
Variable Placebo (n=42) (%) Umifenovir (n=40) (%) t/χ 2 value P value
Age (yrs) 45.50 ± 2.45 42.35 ± 2.38 0.92 0.360
Sex:
Female 14 (33) 9 (23) 1.19 0.275
Male 28 (67) 31 (78)
Height (cm) 164.50 ± 1.06 164.25 ± 1.05 0.17 0.867
Weight (kg) 69.19 ± 1.43 68.40 ± 1.43 0.39 0.697

(C) Moderate patients (n=41)

Variable Placebo (n=21) (%) Umifenovir (n=20) (%) t/χ 2 value P value

Age (yrs) 51.05 ± 3.17 53.55 ± 2.61 0.61 0.548

Sex:
Female 5 (24) 3 (15) 0.51 0.477
Male 16 (76) 17 (85)
Height (cm) 165.57 ± 1.61 168.30 ± 1.00 1.42 0.163
Weight (kg) 70.14 ± 1.14 70.30 ± 1.58 0.08 0.936

Our own hypothesis, based on earlier reports, suggested that To the best of our knowledge, the present trial is the first one
early administration of the drug should be useful for COVID-19 involving Umifenovir against SARS-Cov2 that is double-blinded,
patients and also that the dosage of Umifenovir was much less placebo controlled one. The earlier clinical trials involving Umifen-
than that needed to achieve the Cmax suggested for use against ovir against SARS-Cov2 did not involve placebo control. Further, the
SARS-Cov2. This was also suggested by other studies (Wang et al., dosage in the earlier reported trials did not take into account the
2020). We therefore designed separate primary endpoints for Mild- earlier suggested Cmax of 4.1 μM needed for efficacy of Umifen-
asymptomatic and moderate patients respectively. ovir against SARS-Cov2. A single dose of 800 mg of Umifenovir

65
R. Ramachandran, V. Bhosale, H. Reddy et al. International Journal of Infectious Diseases 115 (2022) 62–69

Figure 2. Time to RT-PCR-negativity in the two groups of Mild-asymptomatic patients. Orange line corresponds to Umifenovir arm while the blue curve corresponds to the
placebo arm.

Table 2
Statistical and RT-PCR negativity summary of Mild-Asymptomatic patients recruited in the clinical trial
(n=82)

RT-PCR test Day (negative) Placebo (n=42) (%) Umifenovir (n=40) (%) Diff (%) P value

5 17 (40) 29 (73) 32 0.002

7 29 (69) 31 (78) 8 0.194
9 33 (79) 36 (90) 11 0.078
11 39 (93) 37 (93) 0 0.475
13 41 (98) 39 (98) 0 0.486
15 41 (98) 40 (100) 2 0.163
17 41 (98) 40 (100) 2 0.163
19 42 (100) 40 (100) 0 -

Figure 3. Reduction in the mean WHO scores plotted in Asymptomatic and Mild patients (n=82). Pink curves represent the reduction in the mean WHO scores on days
0,3,5,7,14,21 and 28 respectively while blue curves depict the reduction in the average WHO scores on the respective days plotted on the X-axis. Significant difference in the
reduction in the mean WHO score was observed on day 5 in the Mild-Asymptomatic patients (P=0.019).

66
R. Ramachandran, V. Bhosale, H. Reddy et al. International Journal of Infectious Diseases 115 (2022) 62–69

Figure 4. Pink lines corresponds to Umifenovir patients in the Moderate category, while blue represents the placebo category. Both sets of patients received the standard-
of-care.

Table 3 Table 4
Average WHO scores tabulated for the Mild-asymptomatic Average WHO scores (Mean ± SE) tabulated for the Moderate
group. group (n=41)

Time Mild-asymptomatic (n=82) Time Moderate (n=41)

(days) Placebo (n=42) Umifenovir (n=40) P value (days) Placebo (n=21) Umifenovir (n=20) P value

day 0 1.76 ± 0.14 1.88 ± 0.15 0.479 day 0 3.57 ± 0.11 3.60 ± 0.11 0.930
day 3 1.21 ± 0.13 0.95 ± 0.12 0.098 day 3 2.95 ± 0.19 2.45 ± 0.22 0.125
day 5 0.88 ± 0.13 0.45 ± 0.11 0.019 day 5 1.95 ± 0.32 1.60 ± 0.32 0.281
day 7 0.45 ± 0.12 0.25 ± 0.09 0.414 day 7 1.24 ± 0.32 1.25 ± 0.32 0.971
day 14 0.07 ± 0.05 0.03 ± 0.02 0.771 day 14 0.57 ± 0.24 0.35 ± 0.20 0.497
day 21 0.00 ± 0.00 0.15 ± 0.15 0.646

in healthy patients were reported to have a Cmax of about 4.1

μM and this corresponds to the IC50 of ∼4.1 μM reported against
SARS-Cov2 for Umifenovir. The reported half-life of ∼14-16 hrs and nausea were reported and this also was distributed almost equally
the good safety profile of the drug led us to rationally propose a between the Umifenovir and standard of care arms respectively. No
dosage of 800mg twice a day for the repurposing strategy involv- negative disease progression was noted in both arms and the pa-
ing Umifenovir against SARS-Cov2. tients steadily improved. No deaths were also reported in either
In the trials, we found that Umifenovir was safe and well toler- arm. This is similar to the reports of minor adverse events in other
ated and only few minor events like headache, stomach ache and trials involving Umifenovir.

Table 5
Tabulation of adverse events.

Category Symptom Number of patients Resolved (Y/N)

Umifenovir group
Asymptomatic Stomach ache 1 Y
Mild Nausea 2 Y
Mild Headache 1 Y
Asymptomatic Nausea with Vomiting 2 Y
Asymptomatic Headache/ Nausea 1 Y
Placebo group
Asymptomatic Stomach ache 1 Y
Mild Nausea 1 Y
Asymptomatic Vomiting 1 Y
Moderate Nausea with Vomiting 1 Y
Moderate Headache/ Nausea 1 Y
Asymptomatic Stomach ache/ headache 1 Y
Mild Stomach ache / Nausea/ Vomiting 1 Y

67
R. Ramachandran, V. Bhosale, H. Reddy et al. International Journal of Infectious Diseases 115 (2022) 62–69

In the present trial the primary endpoint involving asymptotic communicated by CSIR-Central Drug Research Institute with num-
and mild patients was time to nasopharyngeal swab negativity by ber 10317.
two RT-PCR tests for SARS COV2 antigens taken 24 hrs apart from Funding source Council of Scientific and Industrial Research, Min-
the date of randomization. While the secondary endpoint was the istry of Science and Technology, Government of India, funded and
average change in the ordinal scale from the baseline scores from sponsored the study via grant number MLP2038.
randomization on the eight-point ordinal scale as defined by WHO. Ethical approval
In the Mild-asymptomatic patients group (n=82), we found that All required ethical and regulatory approvals were taken before
73% patients on the Umifenovir arm were RT-PCR negative on the the start of the clinical trial. The protocol and informed consent
5th day as compared to only 40% patients on the placebo arm forms were approved by the Drugs Controller General of India and
(P=0.004). Hence the trial meets the primary endpoint criteria for the Institutional ethics committees. All patients gave their written
this patient category. Our confidence in the result for the Mild- informed consent. The trial was conducted as per the guidelines
asymptomatic patients is further bolstered by the post hoc statis- of the Central Drugs Standard Control Organization, the National
tical analysis that was estimated to be 84.5% as compared to the regulatory authority in India.
originally calculated 80%. Statistically significant clinical recovery References
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on the 5th day as assessed by the WHO score analysis (secondary clathrin dependent trafficking. Antivir. Res. 2013; 100:215–219.
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cally better and was captured on days 0 (date of randomization), Boriskin YS, Leneva IA, Pécheur EI, Polyak SJ. Arbidol: a broad-
3, 5,7,14, 21, and 28 respectively. spectrum antiviral compound that blocks viral fusion. Curr Med
For Moderate patients, the average change in the ordinal scale Chem. 2008; 15:997–1005.
from the baseline scores from randomization on the eight-point Chen Y, Liu Q, Guo D. Emerging coronaviruses: genome struc-
ordinal scale as defined by WHO was the primary endpoint. The ture, replication, and pathogenesis. J Med Virol 2020; 92:418–23
baseline scores were similar between the respective placebo and Cheng ZJ, Shan J. 2019 Novel coronavirus: where we are and
Umifenovir arms on day 0. We found that the WHO scores for the what we know. Infection 2020 Available from: https://doi:10.1007/
Umifenovir arm suggested faster improvement as compared to the s15010-15020-01401-y
Placebo arm (P=0.125 on day3) in the moderate patients, but was Darazam IA, Shervin Shokouhi, Masoud Mardani, Mohamad
not statistically significant. However, a limitation of the trial was Amin Pourhoseingholi, Mohammad Mahdi Rabiei, Firouze Hatami,
the smaller number of patients in the moderate patients group, Minoosh Shabani, Omid Moradi, Farid Javandoust Gharehbagh,
and we therefore suggest a larger trial for moderate patients to Seyed Sina Naghibi Irvani, Mahdi Amirdosara, Mohammadreza Ha-
take these results further. jiesmaeili, Omidvar Rezaei, Ali Khoshkar, Legha Lotfollahi, Latif
In view of the safety profile we suggest studies to evaluate Gachkar, Hadiseh Shabanpour Dehbsneh, Negar Khalili, Azam So-
efficacy in children and pregnant/ breast-feeding women too, es- leymaninia, Akram Hoseyni Kusha, Maryam Taleb Shoushtari,
pecially as no other therapeutic is available for this population Parham Torabinavid. Umifenovir in hospitalized moderate to severe
segments. We also recommend future studies for evaluation of COVID-19 patients: A randomized clinical trial Int Immunopharma-
Umifenovir as a prophylactic as this would be useful for high-risk col. 2021;99:107969. doi: 10.1016/j.intimp.2021.107969.
contacts. Both the latter suggestions are supported by the fact that Deng L, Li C, Zeng Q, Liu X, Li X, Zhang H, Hong Z, Xia J, Arbidol
Umifenovir is used as a prophylactic against influenza and also ap- combined with LPV/r versus LPV/r alone against Corona Virus Dis-
proved for use in children and pregnant women. ease 2019: A retrospective cohort study. J Infect. 2020 Mar 11. pii:
Overall, there is an urgent need for effective and safe treat- S0163-4453(20)30113-4. doi: 10.1016/j.jinf.2020.03.002.
ments for COVID-19 patients and our results demonstrate the effi- Huang D, He Yu, Ting Wang, Huan Yang, Rong Yao, and Zon-
cacy and use of Umifenovir in Mild-asymptomatic adult COVID-19 gan Liang Efficacy and safety of umifenovir for coronavirus disease
patients in the dosage tested here. 2019 (COVID-19): A systematic review and meta-analysis J Med Vi-
Contributors rol. 2020: 10.1002/jmv.26256.
TKK, VB, RR, SS, SKR and HR contributed to the study concept Lian N, Xie H, Lin S, et al. Umifenovir treatment is not associ-
and protocol design. HR, VA, MMAF, ZAK, HK, JF, VaS and VS con- ated with improved outcomes in patients with coronavirus disease
tributed to protocol implementation and verified the clinical data 2019: a retrospective study. Clin Microbiol Infect. 2020;26:917-921.
integrity. AS, CBT, NG and NM contributed to the chemistry in- Nojomi M, Yassin Z, Hossein Keyvani, Mahin Jamshidi Makiani,
puts for the study. TKK, RR, VB, SS, PRM, SKR and RKT coordi- Maryam Roham, Azadeh Laali, Nasir Dehghan, Mehrnaz Navaei,
nated the collation of the data. Integrity of the data were indepen- Mitra Ranjbar. Effect of Arbidol (Umifenovir) on COVID-19: a
dently audited by a third party and all the authors had access to randomized controlled trial BMC Infect Dis. 2020; 20:954. doi:
the data. MPSN and MS conducted statistical analysis coordinated 10.1186/s12879-020-05698-w.
by RR and VB. Study was supervised by RR, VB, SS, PRM, SKR and Pécheur E-I, Borisevich V, Halfmann P, Morrey JD, Smee DF,
TKK. Prichard M, et al. The synthetic antiviral drug Arbidol inhibits glob-
Declaration of conflict of interests ally prevalent pathogenic viruses. J Virol. 2016;90:3086–92.
The authors declare no competing or conflict of interests Sun, Y. et al. Pharmacokinetics of single and multiple oral doses
Data sharing of arbidol in healthy Chinese volunteers. Int. J. Clin. Pharmacol.
The study protocol is attached as a supplementary file. Ther. 51, 423–432 (2013).
Individual patient data used in the study is not available. Wang X, Ruiyuan Cao, Huanyu Zhang, Jia Liu, Mingyue Xu, Hen-
Acknowledgements grui Hu, Yufeng Li, Lei Zhao, Wei Li, The anti-influenza virus drug,
M/s Medizest Pharmaceutical Pvt Ltd, Goa, India, is acknowl- arbidol is an efficient inhibitor of SARS-CoV-2 in vitro. Cell Discov-
edged for providing the Umifenovir and placebo tablets used in the ery (2020) 6:28. https://doi.org/10.1038/s41421- 020- 0169- 8
study. The human resources of Product Development Centre (PDC) Wei Gao, Si Chen, Kun Wang, Rongzhang Chen, Qian Guo,
of ICMR, New Delhi were used for the study. We acknowledge Jingjing Lu, Xiaodong Wu, Yanan He, Qiaoyun Yan, Shengyun Wang,
Council of Scientific and Research, Ministry of Science and Technol- Feilong Wang, Li Jin, Jing Hua and Qiang Li Clinical features and
ogy, Government of India for funding the study. This manuscript is efficacy of antiviral drug, Arbidol in 220 nonemergency COVID-19

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