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\begin{document}

\title{Remdesivir: A potential game-changer or just a myth? A Systematic Review
and Meta-analysis}



\author[1]{Dhan Shrestha}%
\author[2]{Pravash Budhathoki}%
\author[3]{Nawazish-i-Husain Syed}%
\author[4]{Era Rawal}%
\author[5]{Sumit Raut}%
\author[6]{Sitaram Khadka}%
\affil[1]{Mangalbare Hospital, Morang}%
\affil[2]{Dr Iwamura Memorial Hospital}%
\affil[3]{University of the Punjab}%
\affil[4]{Kathmandu Medical College}%
\affil[5]{Kathmandu Medical College and Teaching Hospital}%
\affil[6]{Shree Birendra Hospital}%


\vspace{-1em}



  
  \date{May 20, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Aim COVID-19 outbreak spread all over the world and created a public
health catastrophe. Here, we have aimed to conduct a systematic review
and meta-analysis on remdesivir use for COVID-19. Methods We searched
Pubmed, Pubmed Central, Scopus, Embase, clinicaltrials.gov, and preprint
sites and identified ten studies for qualitative and four studies for
quantitative analysis using PRISMA guidelines. The quantitative
synthesis was performed using fixed and random effect models in RevMan
5.4. Heterogeneity was assessed using the I-squared (I2) test. Results
Comparing remdesivir group with placebo or standard of care (SOC) group,
remdesivir reduces 14 days mortality (OR 0.61, CI 0.41- 0.91), need of
mechanical ventilation (OR 0.73, CI 0.54-0.97), and overall severe
adverse effects (OR 0.69, 95\% CI 0.54 to 0.88). There is better
clinical improvement on day 28 (OR 1.59, CI 1.06- 2.39); day 14 clinical
recovery (OR 1.48, CI 1.19-1.84); day 14 discharge rate (OR 1.41, CI
1.15-1.73) among remdesivir groups. Earlier clinical improvement (MD
-2.51, CI -4.16 to -0.85); and clinical recovery (MD -4.69, CI -5.11 to
-4.28) seen among remdesivir group. While no difference on 28 days
mortality rate; discharge rate; overall adverse effect. Longer course
(10 days) of remdesivir showed higher discharge rate at day 14 (OR 2.11,
CI 1.50-2.97), but there are significantly higher rates of serious
adverse effects, and drug discontinuation than the shorter course.
Conclusion Remdesivir showed a better 14 days mortality profile,
clinical recovery, and discharge rate. Overall clinical improvement and
clinical recovery were earlier among remdesivir group.%
\end{abstract}%



\sloppy


\textbf{Title page}

\textbf{Remdesivir: A potential game-changer or just a myth? A
Systematic Review and Meta-analysis}

\textbf{Dhan Bahadur Shrestha \textsuperscript{1}, Pravash
Budhathoki\textsuperscript{2}, Nawazish-i-Husain
Syed\textsuperscript{3*}, Era Rawal\textsuperscript{4}, Sumit
Raut\textsuperscript{4}, Sitaram Khadka\textsuperscript{3,5}}

\textsuperscript{1}Department of Emergency Medicine, Mangalbare
Hospital, Morang-56600, Nepal

\textsuperscript{2}Department of Emergency Medicine, DrIwamura Memorial
Hospital, Bhaktapur-44800, Nepal

\textsuperscript{3}Department of Pharmacology, Punjab University College
of Pharmacy, University of the Punjab, old campus, Lahore-54000,
Pakistan

\textsuperscript{4}Department of Emergency Medicine, Kathmandu Medical
College, Kathmandu-44600, Nepal

\textsuperscript{5}Department of Pharmacy, Shree Birendra Hospital;
Nepalese Army Institute of Health Sciences, Kathmandu-44600, Nepal

\textbf{Short title: Remdesivir in COVID-19}

\textbf{Word count (excluding figure, table and abstract): 3511}

\textbf{Table count: 2}

\textbf{Figure count: 10}

\textbf{*Correspondence}

Professor Dr. Nawazish-i-Husain Syed

Department of Pharmacology,

Punjab University College of Pharmacy,

University of the Punjab, old campus, Lahore-54000, Pakistan

email-nawazish.pharmacy@pu.edu.pk

Mobile \# +92(0)3321413544

\textbf{Declarations}

\textbf{Ethics approval and consent to participate} Not applicable

\textbf{Consent for publication} Not applicable

\textbf{Availability of data and materials} The datasets analyzed during
the current study are available from the corresponding author on
reasonable request.

\textbf{Competing interests} The authors declare that they have no
competing interests.

\textbf{Funding} This article did not receive any specific grant from
funding agencies in the public, commercial, or any other sectors.

\textbf{Authors' contributions} DBS, PB, and SK contributed in concept
and design, analysis, and interpretation of data. DBS, PB, SK, ER and SR
contributed in literature search, data extraction, review and assisted
in analysis. N-i-H S developed the idea and helped in drafting,
supervising and critical reviewing.

All authors were involved in drafting and revising the manuscript and
approved the final version.

\textbf{Authors' information}

\textbf{DBS} Medical officer, Department of Emergency Medicine,
Mangalbare Hospital, Morang, Nepal

\textbf{Email:}\emph{medhan75@gmail.com}

\textbf{ORCid:} \emph{0000-0002-8121-083X}

\textbf{PB} Medical officer, DrIwamura Memorial Hospital, Bhaktapur,
Nepal

\textbf{Email} :\emph{pravash.budhathoki123@gmail.com}

\textbf{ORCid:} 0000-0001-8856-5417

\textbf{N-i-H S} Professor Department of Pharmacology, Punjab University
College of Pharmacy, University of the Punjab, old campus, Lahore-54000,
Pakistan

\textbf{Email} : nawazish.pharmacy@pu.edu.pk

ORCID: 0000-0003-1727-8845

\textbf{ER} Medical officer, Kathmandu Medical College, Kathmandu-44600,
Nepal

\textbf{Email:} erarawal24@gmail.com

\textbf{ORCid:} 0000-0001-9932-1039

\textbf{SR} Medical officer, Kathmandu medical college, Kathmandu,
44600, Nepal

\textbf{Email:} sumitraut179@gmail.com

\textbf{ORCid:} 0000-0001-6090-8027

\textbf{SK} Clinical pharmacologist, Shree Birendra Hospital; Nepalese
Army Institute of Health Sciences, Kathmandu, Nepal

\textbf{Email} :\emph{sitaram.khadka@naihs.edu.np}

\textbf{ORCid:} 0000-0002-0251-3817



\textbf{Remdesivir A potential game-changer or just a myth? A Systematic
Review and Meta-analysis}

\textbf{Research Question}

Research Question: Does remdesivir safely improve the clinical outcome
in patients suffering from COVID- 19?

{\label{research-question-does-remdesivir-safely-improve-the-clinical-outcome-in-patients-suffering-from-covid--19}}

\textbf{ABSTRACT}

\textbf{Aim}

COVID-19 outbreak spread all over the world and created a public health
catastrophe. Here, we have aimed to conduct a systematic review and
meta-analysis on remdesivir use for COVID-19.

\textbf{Methods}

We searched Pubmed, Pubmed Central, Scopus, Embase, clinicaltrials.gov,
and preprint sites and identified ten studies for qualitative and four
studies for quantitative analysis using PRISMA guidelines. The
quantitative synthesis was performed using fixed and random effect
models in RevMan 5.4. Heterogeneity was assessed using the I-squared
(I\textsuperscript{2}) test.

\textbf{Results}

Comparing remdesivir group with placebo or standard of care (SOC) group,
remdesivir reduces 14 days mortality (OR 0.61, CI 0.41- 0.91), need of
mechanical ventilation (OR 0.73, CI 0.54-0.97), and overall severe
adverse effects (OR 0.69, 95\% CI 0.54 to 0.88). There is better
clinical improvement on day 28 (OR 1.59, CI 1.06- 2.39); day 14 clinical
recovery (OR 1.48, CI 1.19-1.84); day 14 discharge rate (OR 1.41, CI
1.15-1.73) among remdesivir groups. Earlier clinical improvement (MD
-2.51, CI -4.16 to -0.85); and clinical recovery (MD -4.69, CI -5.11 to
-4.28) seen among remdesivir group. While no difference on 28 days
mortality rate; discharge rate; overall adverse effect.

Longer course (10 days) of remdesivir showed higher discharge rate at
day 14 (OR 2.11, CI 1.50-2.97), but there are significantly higher rates
of serious adverse effects, and drug discontinuation than the shorter
course.

\textbf{Conclusion}

Remdesivir showed a better 14 days mortality profile, clinical recovery,
and discharge rate. Overall clinical improvement and clinical recovery
were earlier among remdesivir group.

\textbf{Key-words:} Remdesivir, COVID 19, therapeutic efficacy, severe
acute respiratory syndrome coronavirus 2

\textbf{1. Introduction}

COVID-19 outbreak which was first seen in Hubei province of China in
late December of 2019 has become a widespread pandemic. The infection is
caused by a new strain of coronavirus which was later named as Severe
Acute Respiratory Syndrome -- Coronavirus 2 (SARS-CoV 2). The virus has
spread all over the globe and created a public health catastrophe
meanwhile dragging several countries into economic crisis. The symptoms
of infection range from mild viral illness symptoms including sore
throat, headache, cough, fever to severe symptoms of pneumonia and ARDS.
As of August 28 2020, 24 million cases have been confirmed and more than
800,000 deaths have been recorded due to COVID-19 {[}1{]}. However, a
lack of standardized treatment makes the situation even more frightful.
While several trials are being conducted everywhere there are no
specific answers yet. Remdesivir is being used as one of the repurposed
drugs in combating the illness all around the world.

Remdesivir, a nucleotide analogue pro-drug that inhibits viral RNA
polymerases, has shown in vitro activity against SARS-CoV-2 {[}2{]}.
This agent was originally evaluated in 2014 to thwart the Ebola
outbreak. Subsequent evaluation by numerous virology laboratories
demonstrated the ability of remdesivir to inhibit coronavirus
replication, including SARS-CoV-2 {[}3{]}. As a nucleoside analog,
remdesivir acts as an RNA dependent RNA polymerase (RdRp) inhibitor,
targeting the viral genome replication process. The RdRp is the protein
complex coronaviruses use to replicate their RNA-based genomes. After
the host metabolizes remdesivir into active NTP, the metabolite competes
with adenosine triphosphate (ATP: the natural nucleotide normally used
in this process) for incorporation into the nascent RNA strand. In
addition, the drug is believed to outpace the proofreading property of
the virus, thus maintaining the antiviral activity {[}4{]}, {[}5{]}. The
WHO has considered this drug as one of the promising therapeutics
against fighting COVID-19. Multiple clinical trials are underway on the
use of remdesivir for treatment of COVID-19 in the USA and all around
the world {[}6{]}.

We aimed to search for clinical evidence to support the use of
remdesivir regarding its safety and side effects to actually find out
whether the drug is a real game changer or just another drug being used
in vain.

\textbf{2. Objective}

To assess therapeutic efficacy in terms of clinical improvement and
recovery, treatment outcome, need for mechanical ventilation and
respiratory support, along with side effects following treatment with
remdesivir in COVID-19.

\textbf{3. METHODS}

PRISMA guideline was used for our systematic review {[}7{]}.

\textbf{3.1 Criteria for considering studies for this review}

\textbf{3.1.1 Types of studies}

We included the studies focusing on mortality rate, clinical improvement
and recovery, discharge rate, adverse effects, mechanical ventilation,
and respiratory support, mean difference of clinical improvement as well
recovery among patients taking remdesivir compared to the patients
receiving standard of care alone. Also we included studies comparing
longer regimen and shorter regimen of remdesivir comparing above
outcomes.

\textbf{3.1.2 Types of participants}

We included patients diagnosed with COVID-19 who received remdesivir in
addition to the standard of care (SOC) or only receiving standard of
care or placebo with comparison made with remdesivir group.

\textbf{3.1.3 Types of interventions}

Our treatment arm consists of patients taking remdesivir along with the
SOC while the control arm consists of patients receiving SOC or placebo.

\textbf{3.1.4 Types of outcome measures}

For our quantitative analysis, mortality, clinical improvement and
recovery, discharge rate, mechanical ventilation, and respiratory
support, adverse effects, mean difference of clinical improvement as
well recovery and treatment outcome at day 14 and day 28 among the
treatment and control group that occurred during treatment were outcomes
of interest.

\textbf{3.1.5 Outcomes}

We compared mortality, clinical improvement and recovery, discharge
rate, mechanical ventilation, and respiratory support, adverse effects,
mean difference of clinical improvement as well recovery and treatment
outcome at day 14, and day 28 between treatment and control arms. Also,
we compared the longer regimen and shorter regimen of remdesivir for
above outcomes.

\textbf{3.2 Search methods for identification of studies}

Pubmed, PubMed Central, Embase, Scopus, and preprint servers like
medRxiv and bioRxiv were accessed by our reviewers (PB and DBS) who
independently searched and evaluated the quality of the studies till
August 25, 2020. We filtered the studies using COVIDENCE and extracted
data for quantitative and qualitative synthesis. Any potential conflict
was solved taking the final opinion of another reviewer (SK). Another
reviewer (ER) assessed the risk of bias and cross-checked all the
selected studies.

\textbf{3.2.1 Electronic searches}

We have documented the detailed search strategy in Supplementary file
no. 1.

\textbf{3.3 Data collection and analysis}

We extracted the data for quantitative synthesis through COVIDENCE and
did the analysis using RevMan 5.4. Assessment of heterogeneity was done
using the I-squared (I\textsuperscript{2}) test. We used a random/fixed
effect for pooling of selected studies.

\textbf{3.3.1 Selection of studies}

We have included RCTs, prospective, and retrospective observational
studies in which the patients received remdesivir for the treatment of
COVID-19 in the qualitative analysis. For the quantitative analysis, we
included only RCTs with a treatment arm and a control arm. We excluded
studies in which remdesivir was used for treatment among the pediatric
age group, pregnant women, patients with AIDS, end-stage liver disease,
and cancer in the entire study population. We excluded meta-analysis,
reviews, protocols, in-silico studies, AI-based simulation studies, and
the studies in which the outcome was not properly defined among the
patients treated with remdesivir.

\textbf{3.3.2 Data extraction and management}

We evaluated the quality of studies thoroughly and also took into
account only the outcomes that were of our interest.

\textbf{3.3.3 Assessment of risk of bias in included studies}

We used the Cochrane ROB 2.0 tool for analysis of our RCTs shown in
figure 1 {[}8{]}. We used the NHLBI (National Heart, Lung, and Blood
Institute) quality assessment tools to assess the risk of bias in our
prospective and retrospective observational studies (Table 1) {[}9{]}.
We used RevMan 5.4 for creating a summary of biases for RCTs using the
Cochrane ROB 2.0 tool.

\textbf{Figure 1} : Risk of bias assessment of trials

\textbf{Table 1:} NHLBI assessment of bias for observational studies

\textbf{3.3.4 Assessment of heterogeneity}

TheI-squared (I\textsuperscript{2}) test was used for the assessment of
heterogeneity. We interpreted the I-squared (I\textsuperscript{2}) test
done based on the Cochrane Handbook for Systematic Reviews of
Interventions as follows\textsuperscript{15}: -

i) 0\% to 40\%: might not be important

ii) 30\% to 60\%: may represent moderate heterogeneity

iii) 50\% to 90\%: may represent substantial heterogeneity

iv) 75\% to 100\%: considerable heterogeneity.

The importance of the observed value of I\textsuperscript{2} depends on
(i) magnitude and direction of effects and (ii) strength of evidence for
heterogeneity (e.g. P-value from the chi-squared test, or a confidence
interval for I\textsuperscript{2}).''

\textbf{3.3.5 Assessment of reporting biases}

Reporting bias was checked by prefixed reporting of the outcome.

\textbf{3.3.6 Data synthesis}

Statistical analysis was performed using RevMan 5.4 software. Risk Ratio
(RR)/ Odds Ratio (OR) was used for outcome estimation whenever
appropriate with 95\% Confidence Interval (CI). The fixed/random-effects
model was used according to heterogeneities. We analyzed the mean
differences among the two groups for the duration of clinical
improvement and recovery using the median, sample size, and
interquartile range whenever the means and standard deviations were not
provided in the study {[}16{]}.

\textbf{3.3.7 Subgroup analysis and investigation of heterogeneity}

We used the random effect model, in cases of heterogeneity.

\textbf{3.3.8 Sensitivity analysis}

We did not run sensitivity analysis being there were only three RCTs
comparing remdesivir with SOC and two only comparing shorter and longer
regimen of remdesivir. Also there is low-moderate heterogeneity in most
fields of our analysis so sensitivity analysis was not used.

\textbf{4. RESULTS}

\textbf{A. Qualitative synthesis}

We identified a total of 5573 studies after electronic database
searching. We removed 600 duplicates. Screening of the title and
abstracts of 4973 studies was done. We excluded 4942 studies and checked
31 articles for full-text eligibility. We excluded 21 studies with
definite reasons mentioned in the PRISMA flow diagram in figure 2. At
last, 10 studies were selected for qualitative analysis. A discussion of
these studies is done in table 2.

\textbf{Figure 2:} PRISMA flow chart

\textbf{Table 2: Qualitative analysis}

\textbf{B. Quantitative synthesis}

Overall 4 RCTs are included in the quantitative synthesis.

\textbf{4.1. Treatment outcome}

We have compared outcomes of randomized studies with different duration
of remdesivirversus placebo or standard of care (SOC). Mortality rate,
clinical improvement ([?]2-point improvement in the ordinal score),
clinical recovery (an improvement from a baseline score of 2 to 5 to a
score of 6 or 7 or from a baseline score of 6 to a score of 7 in the
ordinal score),and discharge rate were our primary outcome variables.
Development of adverse effects (severe, overall and grade [?]3 adverse
event), invasive and non-invasive mechanical ventilation requirement,
and mean duration of clinical recovery and improvement were our
secondary outcome variables between remdesivir versus placebo or
standard of care (SOC) and shorter (5 days) versus longer (10 days) use
ofremdesivir. Among the included studies meta-analysis, we found there
is low-high heterogeneity, may be due to different study design,
biological variability among studies, and risk of bias among studies
that could not be omitted fully.

\textbf{4.1.1 Remdesivir versus placebo or standard of care: Mortality
rate}

The meta-analysis of odds ratios (OR) for remdesivir compared with
placebo or SOC using fixed effect model among three randomized studies
showed that remdesivir reduces 14 days mortality (OR 0.61, 95\% CI 0.41
to 0.91; participants = 1688; studies = 3; I\textsuperscript{2} = 0\%).
Meanwhile, there is no significant difference between two groups for 28
days mortality (OR 1.02, 95\% CI 0.50 to 2.06; participants = 629;
studies = 2; I\textsuperscript{2} = 0\%) (Fig. 3).

\textbf{Figure 3.} Forest plot for mortality comparing remdesivir versus
placebo or standard of care

\textbf{4.1.2 Remdesivir versus placebo or standard of care: Clinical
improvement and recovery}

Meta-analysis for clinical improvement ([?]2-point improvement in ordinal
score) showed slight improvement with statistical significance only in
day 28. (Day 14; OR 1.45, 95\% CI 1.00 to 2.08; participants = 629;
studies = 2; I\textsuperscript{2} = 0\%; Day 28; OR 1.59, 95\% CI 1.06
to 2.39; participants = 629; studies = 2; I\textsuperscript{2} = 0\%)
(Fig. 4). Similarly, there is clinically significant clinical recovery
in day 14 among remdesivir groups compared to placebo or SOC (OR 1.48,
95\% CI 1.19 to 1.84; participants = 1452; studies = 2;
I\textsuperscript{2} = 0\%) (Fig. 5).

\textbf{Figure 4.} Forest plot for clinical improvement comparing
remdesivir versus placebo or standard of care

\textbf{Figure 5.} Forest plot for clinical recovery comparing
remdesivir versus placebo or standard of care

\textbf{4.1.3 Remdesivir versus placebo or standard of care: Discharge
rate}

Result on discharge rate showed increased discharge rate among
remdesivir group both in 14 days and 28 days but it is statistically
significant for 14 days only (day 14; OR 1.41, 95\% CI 1.15 to 1.73;
participants = 1688; studies = 3; I\textsuperscript{2} = 0\%; day 28; OR
1.35, 95\% CI 0.91 to 2.02; participants = 629; studies = 2;
I\textsuperscript{2} = 53\%) (Fig. 6).

\textbf{Figure 6.} Forest plot for discharge rate comparing remdesivir
versus placebo or standard of care

\textbf{4.2 Remdesivir versus placebo or standard of care: Adverse
effects}

The meta-analysis of three randomized controlled trials showed that the
odds of having severe adverse effects is less among remdesivir group (OR
0.69, 95\% CI 0.54 to 0.88; participants = 1688; studies = 3;
I\textsuperscript{2} = 0\%) though odds for the development of overall
adverse effect (OR 1.10, 95\% CI 0.70 to 1.72; participants = 1688;
studies = 3; I\textsuperscript{2} = 74\%) and grade [?]3 adverse event (OR
0.85, 95\% CI 0.52 to 1.38; participants = 629; studies = 2;
I\textsuperscript{2} = 32\%) among two groups is statistically
insignificant (Fig. 7).It is also important to note that the
discontinuation of the drug(due to adverse effects in patients) is not
significant among the groups. (OR 1.26, 95\% CI 0.50 to 3.19)
(Supplementary file 3. Fig. 1).

\textbf{Figure 7.} Forest plot for adverse events comparing remdesivir
versus placebo or standard of care

\textbf{4.3 Remdesivir versus placebo or standard of care: Mechanical
ventilation and respiratory support}

Meta-analysis of baseline mechanical ventilation and respiratory support
among included studies showed no statistical differences between two
arms (OR 0.87, 95\% CI 0.71 to 1.06; participants = 2991; studies = 5;
I\textsuperscript{2} = 16\%). Also there is no difference for both NIMV
and high-flow oxygen (OR 1.01, 95\% CI 0.76 to 1.34; participants =
1692; studies = 3; I\textsuperscript{2} = 0\%) and IMV or ECMO (OR 0.76,
95\% CI 0.57 to 1.00; participants = 1299; studies = 2;
I\textsuperscript{2} = 0\%) (Supplementary file 3. Fig. 2).

But, at 14 days, the need for mechanical ventilation and respiratory
support is significantly lower among remdesivir groups (OR 0.73, 95\% CI
0.54 to 0.97; participants = 3377; studies = 6; I\textsuperscript{2} =
27\%). On subgroup analysis the result support for IMV or ECMO
requirement (OR 0.69, 95\% CI 0.49 to 0.97; participants = 1689; studies
= 3; I\textsuperscript{2} = 49\%). While for NIMV and high-flow oxygen
it is of no statistical significance (OR 0.84, 95\% CI 0.49 to 1.45;
participants = 1688; studies = 3; I\textsuperscript{2} = 16\%) (Fig. 8).

\textbf{Figure 8.} Forest plot for day 14 ventilation and respiratory
support comparing remdesivir versus placebo or standard of care

\textbf{4.4 Remdesivir versus placebo or standard of care: Mean
differences of duration of clinical improvement and recovery}

Meta-analysis on clinical improvement ([?]2-point improvement in ordinal
score) showed clinical improvement among remdesivir group (MD -2.51,
95\% CI -4.16 to -0.85; participants = 629; studies = 2;
I\textsuperscript{2} = 10\%) approximately 2.5 days earlier. While
clinical recovery (an improvement from a baseline score of 2-5 to a
score of 6 or 7 or from a baseline score of 6 to a score of 7 in the
ordinal score) was seen about 4.5 days earlier among remdesivir group
(MD -4.69, 95\% CI -5.11 to -4.28; participants = 1452; studies = 2;
I\textsuperscript{2} = 97\%) (Fig. 9).

\textbf{Figure 9.} Forest plot of mean differences of duration of
clinical improvement and recovery among remdesivir group versus placebo
or SOC

\textbf{4.5 Treatment outcome at day 14: Remdesivir shorter (5 days) vs
longer (10 days) course of treatment}

Meta-analysis comparing the longer 10 days course of remdesivir with
shorter five days course showed higher discharge rate at day 14 (OR
2.11, 95\% CI 1.50 to 2.97; participants = 781; studies = 2;
I\textsuperscript{2} = 96\%). But there is significantly higher rates of
serious adverse effects (OR 1.77, 95\% CI 1.19 to 2.65; participants =
781; studies = 2; I\textsuperscript{2} = 20\%), grade [?]3 adverse event
(OR 1.53, 95\% CI 1.09 to 2.16; participants = 781; studies = 2;
I\textsuperscript{2} = 0\%), and drug discontinuation due to medication
intolerance (OR 2.74, 95\% CI 1.06 to 7.07, participants = 781, studies
= 2, I\textsuperscript{2} = 0\%) among longer (10 days) course than
shorter (5 days) treatment group. Also IMV or ECMO requirement is higher
among longer (10 days) course group (OR 2.34, 95\% CI 1.26 to 4.35,
participants = 781, studies = 2, I\textsuperscript{2} = 0\%) than
shorter (5 days) remdesivir group.

There is no statistical significance among two groups for overall 14
days mortality rate (OR 1.41, 95\% CI 0.73 to 2.72, participants = 781,
studies = 2, I\textsuperscript{2} = 0\%), clinical improvement at 14
days (OR 0.79, 95\% CI 0.58 to 1.07, participants = 781, studies = 2,
I\textsuperscript{2} = 48\%), clinical recovery (OR 0.75, 95\% CI 0.55
to 1.02, participants = 781, studies = 2, I\textsuperscript{2} = 31\%),
overall adverse effects (OR 1.26, 95\% CI 0.93 to 1.69, participants =
781, studies = 2, I\textsuperscript{2} = 0\%), and NIMV or high flow
oxygen requirement (OR 0.78, 95\% CI 0.34 to 1.77, participants = 781,
studies = 2, I\textsuperscript{2} = 58\%) (Fig 10).

\textbf{Figure 10.} Forest plot of treatment outcome at day 14:
Remdesivir shorter (5 days) vs longer (10 days) course of treatment

\textbf{C. Clinical trials}

A total of 48 trials for the assessment of Remdesivir on COVID-19 has
been registered until now in ClinicalTrials.gov (ClinicalTrials.gov)
(Supplementary file 4.) {[}6{]}. In most cases,these trials are being
conducted with the primary outcome of time to recovery, mortality,
clinical improvement, and need for mechanical ventilation. Including the
United States (23 trials), France (4 trials),a total of 15 countries
(among the locations provided) are managing such trials around the
globe. One of them in France has an enrollment of 6 hundred thousand
participants as the largest type. Total of 38 trials are clinical trials
while the rest of the trials are of observational types or expanded
access. Twenty-six of such trials are recruiting participants. A total
of 10 trials are not yet recruiting participants, whereas 1 trial is
active but not recruiting participants. A trial run in the US is in a
status of enrolling by invitation. Among the rest, 2 are available and 1
each is withdrawn, suspended and terminated.

\textbf{5. Discussion}

Although multiple studies are conducted around the world there is no
specific treatment that proves to be efficacious with minimal adverse
effects. To obtain precise evidence to date, this meta-analysis is
conducted with available four RCTs to gauge the effectiveness of
remdesivir in comparison to placebo or standard of care.

Our meta-analysis of odds ratio showed reduced 14-day mortality (OR
0.61, 95\% CI 0.41 to 0.91) in patients taking remdesivir for ten days,
whereas no significant difference in 28 days mortality between
remdesivir groups and SOC or placebo (OR 1.02, 95\% CI 0.50 to 2.06). In
contrast, Piscayo et al. showed no reduction of all-cause mortality in
14 days (RR 0.71, 95\% CI 0.39 to 1.28) {[}21{]}. This may be due to
inclusion of data from Spinner CD et al. in the present meta-analysis,
which was not there in Piscayo et al{[}21{]}. Meta-analysis of clinical
recovery on day 14 and 28 were clinically and statistically significant
in favor of patients taking remdesivir in comparison to placebo or
standard of care (day 14: OR 1.48, 95\% CI 1.19 to 1.84; day 28: OR
2.09, 95\% CI 1.09 to 4.03). The findings are concurrent with Piscoya et
al.{[}21{]}. Findings on discharge rate on day 14 and 28 were higher
among the remdesivir group, but it is statistically insignificant on day
28. Analysis of clinical improvement showed approximately 2.5 days
earlier improvement among the Remdesivir group than SOC. Zhu et al also
showed similar findings with the discharge rate that was reflective of
the patient's recovery and clinical outcome {[}22{]}. A higher discharge
rate was seen with 10 days use of remdesivir in comparison to 5 days.
However, the difference in clinical improvement was not significant with
5 days and 10 days' use of drugs.

Severe adverse effects occurrence was less with remdesivir use in
comparison with placebo or SOC, but its use for 10 days showed increased
severe adverse effects, grade [?]3 adverse effect, and drug
discontinuation in comparison with 5 days use. The overall adverse
effect was less with placebo but it was statistically insignificant.
Alexander et al.study also showed less severe adverse effect with
remdesivir use with fixed-effect modeling but this result appeared
statistically insignificant with random-effect modeling in their study
{[}23{]}.

Based on our meta-analysis, the need for mechanical ventilation and
respiratory support at day 14 was significantly less with remdesivir,
which was also supported with subgroup analysis among IMV and ECMO
receiving patients, whereas among NIMV and high-flow oxygen receiving
patients it was of no significance. Also, the 10 days course of the drug
showed the increased requirement of ECMO and IMV in contrast to the 5
days drug course. Piscoya et al. study showed no significant decrease in
the requirement of invasive ventilation with remdesivir (RR 0.57, 95\%
CI 0.23 to 1.42) {[}21{]}.

In present meta-analysis, remdesivir showed a statistically significant
reduction in 14-day mortality, speedy clinical improvement/ recovery
leading to discharge, less requirement of the ventilator with a lesser
degree of severe adverse events compared with placebo or SOC. Alike
remdesivir many other drugs were repurposed as candidate treatment
options for COVID-19. A study was done by Shrestha et al. on
favipiravir- another potential candidate drug that showed significant
results on clinical improvement at day 14 (RR 1.41, 95\% CI 1.10 to
1.80) {[}24{]}. Many other potential treatment options like
corticosteroids, convalescent plasma therapy,and hydroxyl-choloroquine
showed mixed results in individual studies.

The available RCTs and meta-analysis still show a contrasting outcome
with remdesivir. Although we have included four RCTs, they have several
limitations, and also, the presence of heterogeneity among studies.Also,
non-uniform treatment options lead to some difficulties comparing them.
Few evident biases and issues were due to lack of complete follow-up,
early reporting, and additional use of several therapeutic agents as
supportive care. These all lead to some discrepancy in the study results
and uncertainty on findings regarding the result of remdesivir use.
Safety and efficacy of remdesivir in COVID-19 patients is still dubious.
Henceforth, we believe that these findings should be supported by
undergoing large scale double-blinded RCTs to increase the confidence of
remdesivir use in COVID-19.

\textbf{6. Conclusion}

Remdesivir has been shown to enhance recovery with reduced oxygen
support and better clinical outcome and decrease mortality among
patients with COVID 19. However, the current studies are mostly
open-label studies with a small sample size. Despite early promise,
further ongoing large scale trials results should be awaited to make a
full decision.

\textbf{Acknowledgements} Not applicable

\textbf{Figure legends}

\textbf{Figure 1} : Risk of bias assessment of trials

\textbf{Figure 2:} PRISMA flow chart

\textbf{Figure 3.} Forest plot for mortality comparing remdesivir versus
placebo or standard of care

\textbf{Figure 4.} Forest plot for clinical improvement comparing
remdesivir versus placebo or standard of care

\textbf{Figure 5.} Forest plot for clinical recovery comparing
remdesivir versus placebo or standard of care

\textbf{Figure 6.} Forest plot for discharge rate comparing remdesivir
versus placebo or standard of care

\textbf{Figure 7.} Forest plot for adverse events comparing remdesivir
versus placebo or standard of care

\textbf{Figure 8.} Forest plot for day 14 ventilation and respiratory
support comparing remdesivir versus placebo or standard of care

\textbf{Figure 9.} Forest plot of mean differences of duration of
clinical improvement and recovery among remdesivir group versus placebo
or SOC

\textbf{Figure 10.} Forest plot of treatment outcome at day 14:
Remdesivir shorter (5 days) vs longer (10 days) course of treatment

\textbf{List of tables}

\textbf{Table 1} : NHLBI assessment of observational studies and case
series

\textbf{Table 2} : Qualitative table

\textbf{List of supplementary files}

\textbf{Supplementary file 1:} Search strategy

\textbf{Supplementary file 2:} NHLBI Bias of observational and case
series

\textbf{Supplementary file 3:} Synthesis and sensitivity assessment

\textbf{Supplementary file 4:} Clinical trials

\textbf{Supplementary file 5:} Prisma checklist

\textbf{7. References:-}

1. Worldometer. Coronavirus Cases. \emph{Worldometer} . 2020:1-22.

2. Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir
for Patients with Severe Covid-19. \emph{New England Journal of
Medicine} . 2020;382(24):2327-2336. doi:10.1056/NEJMoa2007016

3. Eastman RT, Roth JS, Brimacombe KR, et al. Remdesivir: A Review of
Its Discovery and Development Leading to Emergency Use Authorization for
Treatment of COVID-19. \emph{ACS Central Science} . 2020;6(5):672-683.
doi:10.1021/acscentsci.0c00489

4. Amirian ES, Levy JK. Current knowledge about the antivirals
remdesivir (GS-5734) and GS-441524 as therapeutic options for
coronaviruses. \emph{One Health} . 2020;9:100128.
doi:10.1016/j.onehlt.2020.100128

5. Gordon CJ, Tchesnokov EP, Feng JY, Porter DP, G\selectlanguage{ngerman}ötte M. The antiviral
compound remdesivir potently inhibits RNAdependent RNA polymerase from
Middle East respiratory syndrome coronavirus. \emph{Journal of
Biological Chemistry} . 2020;295(15):4773-4779.
doi:10.1074/jbc.AC120.013056

6. Search of: Recruiting, Not yet recruiting, Active, not recruiting,
Enrolling by invitation Studies \textbar{} Coronavirus - List Results -
ClinicalTrials.gov.\emph{https://clinicaltrials.gov/ct2/results?cond=Coronavirus\&recrs=b\&recrs=a\&recrs=f\&recrs=d\&age\_v=\&gndr=\&type=\&rslt=\&Search=Apply}.
Accessed August 29, 2020.

7. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for
reporting systematic reviews and meta-analyses of studies that evaluate
healthcare interventions: explanation and elaboration. \emph{BMJ
(Clinical research ed)} . 2009;339. doi:10.1136/bmj.b2700

8. RoB 2.0: A revised tool to assess risk of bias in randomized trials
{[}webinar{]} \textbar{} Cochrane
Training.\emph{https://training.cochrane.org/resource/rob-20-webinar}.
Accessed August 28, 2020.

9. Study Quality Assessment Tools \textbar{} NHLBI,
NIH.\emph{https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools}.
Accessed August 28, 2020.

10. Anderson MR, Bach PB, Baldwin MR. Hospital length of stay for severe
COVID-19 patients: implications for Remdesivir's value. \emph{medRxiv} .
August 2020:2020.08.10.20171637. doi:10.1101/2020.08.10.20171637

11. Antinori S, Cossu MV, Ridolfo AL, et al. Compassionate remdesivir
treatment of severe Covid-19 pneumonia in intensive care unit (ICU) and
Non-ICU patients: Clinical outcome and differences in post-treatment
hospitalisation status. \emph{Pharmacological Research} .
2020;158:104899. doi:10.1016/j.phrs.2020.104899

12. Augustin M, Hallek M, Nitschmann S. Remdesivir for patients with
severe COVID-19. \emph{Internist} . 2020;61(6):644-645.
doi:10.1007/s00108-020-00800-5

13. Olender SA, Perez KK, Go AS, et al. Remdesivir for Severe COVID-19
versus a Cohort Receiving Standard of Care. \emph{Clinical Infectious
Diseases} . July 2020. doi:10.1093/cid/ciaa1041

14. Pasquini Z, Montalti R, Temperoni C, et al. OUP accepted
manuscript.\emph{Journal of Antimicrobial Chemotherapy} . 2020.
doi:10.1093/jac/dkaa321

15. Cochrane Handbook for Systematic Reviews of Interventions \textbar{}
Cochrane Training.\emph{https://training.cochrane.org/handbook}.
Accessed August 28, 2020.

16. Mean Variance
Estimation.\emph{https://web.archive.org/web/20181224162602/http:/www.comp.hkbu.edu.hk/\textasciitilde{}xwan/median2mean.html}.
Accessed August 29, 2020.

17. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment
of Covid-19 --- Preliminary Report. \emph{New England Journal of
Medicine} . May 2020. doi:10.1056/nejmoa2007764

18. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 Days in
Patients with Severe Covid-19. \emph{New England Journal of Medicine} .
May 2020. doi:10.1056/nejmoa2015301

19. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of Remdesivirvs
Standard Care on Clinical Status at 11 Days in Patients With Moderate
COVID-19: A Randomized Clinical Trial. \emph{JAMA} . August 2020.
doi:10.1001/jama.2020.16349

20. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe
COVID-19: a randomised, double-blind, placebo-controlled, multicentre
trial. \emph{The Lancet} . 2020;395(10236):1569-1578.
doi:10.1016/S0140-6736(20)31022-9

21. Piscoya A, Ng-Sueng LF, Parra del Riego A, et al. Efficacy and harms
of remdesivir for the treatment of COVID-19: a systematic review and
meta-analysis. \emph{medRxiv} . May 2020:2020.05.26.20109595.
doi:10.1101/2020.05.26.20109595

22. Zhu Y, Teng Z, Yang L, et al. Efficacy and Safety of Remdesivir for
COVID-19 Treatment: An Analysis of Randomized, Double-Blind,
Placebo-Controlled Trials. \emph{medRxiv} . June
2020:2020.06.22.20136531. doi:10.1101/2020.06.22.20136531

23. Alexander PE, Piticaru J, Lewis K, et al. Remdesivir use in patients
with coronavirus COVID-19 disease: a systematic review and
meta-analysis. \emph{medRxiv} . May 2020:2020.05.23.20110932.
doi:10.1101/2020.05.23.20110932

24. Shrestha DB, Budhathoki P, Khadka S, Shah PB, Pokharel N, Rashmi P.
Favipiravirversus other antiviral or standard of care for COVID-19
treatment: A rapid systematic review and meta-analysis. July 2020.
doi:10.21203/rs.3.rs-40775/v1\selectlanguage{english}
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