1. Comparison of Time to Clinical Improvement With
vs Without Remdesivir
Treatment in Hospitalized Patients With COVID-19
JOURNAL CLUB EVALUATION
PHAR
ZEINAB NOORMONAVAR
05212021
1
3. Outline
At the end of the presentation we’ll be able to:
Recall the pathophysiology, diagnosis, symptoms, epidemiology, causes of COVID-19
Identify the classification and pharmacological treatment modalities
Learn the different drugs used
Evaluate the journal and methodology used in this article and the results achieved
3
4. Definition
4
A coronavirus identified in 2019,
SARS-CoV-2, has caused a pandemic
of respiratory illness, called COVID-19.
It rapidly spread, resulting in an
epidemic throughout China, followed
by a global pandemic.
The coronavirus can be spread from
person to person. It is diagnosed with
a laboratory test.
COVID-19 can be severe, and has
caused millions of deaths around the
world as well as lasting health
problems in some who have survived
the illness.
https://www.hopkinsmedicine.org/health/conditions-and-diseases/coronavirus
5. 5
Epidemiology
According to WHO study:
In Lebanon, from 3 January 2020 to 22 May
2021, there have been 537,887 confirmed
cases of COVID-19
Number of death: 7,664
As of 16 May 2021, a total of 606,294 vaccine
doses have been administered.
Incidence rate of 208/million persons.
Death rate of 5/million persons (0.0005).
https://covid19.who.int/region/emro/country/lb https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358300/
12. https://www.covid19treatmentguidelines.nih.gov/therapeutic-management/
12
Other recommendation:
• In the United States, the FDA issued an EUA
for Baricitinib (4 mg orally once daily for up to
14 days) to be used in combination
with Remdesivir in patients with COVID-19
who require oxygen or ventilator support.
(reduced time to recovery)
• Tocilizumab (8 mg/kg as a single dose) for
individuals who require high-flow oxygen or
more intensive respiratory support and who
are within 24 to 48 hours of admission to an
intensive care (ICU) or receipt of ICU-level
care. (Incase of elevation of inflammatory
marker: D-Dimer, IL-6, Ferritin)
https://www.uptodate.com/contents/covid-19-management-in-hospitalized-
adults?search=covid%2019%20&source=search_result&selectedTitle=2~150&usage_type=defau
lt&display_rank=2#H2290242517
13. Drugs Used
13
Monoclonal
Antibody
Bamlanivib +
Etesevimab
Casirivimab +
Imdevimab
Tocilizumab
Antiviral
Remdesivir
Anti-
Inflammatory
Dexamethasone
Anticoagulant
Enoxaparin
DMARD
Baricitinib
Injection site rxn
URTI
Nasopharyngitis
Back pain, cough, chest-
tightness, dark color urine
Blurred vision, weight
gain, numbness, fluid &
electrolyte disturbance
Hemorrhage, fever,
thrombocytopenia,
anemia, ALT/AST elevation
URTI, Nausea, platelet
elevation, increased LFTs,
hypersensitivity
Side effect
https://www.medscape.com/pharmacists
Initially: IV infusion of 200mg
then 100 mg IV/d
6 mg PO/IV qDay for up to
10 days
15. Journal Evaluation
15
• JAMA Network Open is an international, peer-reviewed, open access, general medical journal that
publishes research and commentary on clinical care, innovation in health care, health policy, and global
health across all health disciplines and countries for clinicians, investigators, and policy makers.
• Is a monthly open access medical journal published by the American Medical Association covering all
aspects of the biomedical sciences.
• It was established in 2018
• The journal is funded by article processing charges and most articles are available under a Creative
Commons license.
16. Journal Evaluation (Cont’d)
• Article titles and abstracts are translated into Spanish and Chinese.
• Impact factor of 5.032 (2019)
• Ranking: 19th out of 165 journals in the category "Medicine, General & Internal“
4th among purely open access journals in that subject category.
• Published online weekly, every Friday.
• More than 109 million annual online visits.
• Indexing in PubMed/MEDLINE, Science Citation Index Expanded, Journal Citation Reports, and the Directory of
Open Access Journals.
16
19. Title Evaluation
19
Missing Strength
To be
Retrospective Multi-center,
Randomized Clinical Trial Of
Comparison Of Time To Clinical
Improvement With vs Without
Remdesivir(100 mg/qD IV)
Treatment In Hospitalized
Patients With Covid-19 In JHHS
(US)
20. Authors and Authors Evaluation
Most of the authors are
physicians specialized in lung
infectious diseases.
All authors have participated
in other studies and
publications related to lung &
infectious disorder.
Their information are easily
accessible to anyone.
No affiliation with
pharmaceutical company.
There are enough number of
statistician for the accuracy of
study
20
•Brian Garibaldi is an associate professor in the Division of Pulmonary and
Critical Care Medicine, where he attends in the Medical Intensive Care Unit
(MICU) and the Interstitial Lung Disease clinic.
•He is medical director of the Johns Hopkins Biocontainment Unit (BCU), a
federally-funded special pathogens treatment center. He is also the associate
program director of the Osler Medical Residency Program, where he leads
curriculum development and implementation.
Brian T.
Garibaldi
•Matthew Robinson, MD, is Assistant Professor in the Division of Infectious
Diseases at Johns Hopkins University School of Medicine, and he serves on
the Advisory Team for the and serves on the Advisory Team for the Johns
Hopkins Precision Medicine Center of Excellence for COVID-19.
•His research focuses on the diagnosis of acute febrile illness and its
implication on antimicrobial stewardship and resistance in tropical low-
and middle-income countries.
Matthew L.
Robinson
• Mei-Cheng Wang is a Taiwanese biostatistician in the Johns
Hopkins Bloomberg School of Public Health.
• Her research includes both theoretical work on survival
analysis and statistical truncation, and applications to medical
questions including prenatal and infant care, AIDS infection,
and kidney disease.
G. Caleb
Alexander
22. Abstract Evaluation
22
The Rational behind study is clearly stated and is
similar to the one in the article.
• Study design and characteristic are mentioned.
• The number of patients included.
• Variables also are mentioned.
• Length of study is mentioned.
Are similar to the one in article.
Primary, Secondary efficacy outcomes are
mentioned.
The result paralleled to the objective and the
same CI as well as the number of patients included
in trial.
But Side Effects are not mentioned.
P-values is not used in this study.
• Conclusion is the same as in the article.
• No clinical recommendation.
23. Introduction Evaluation
23
The pandemic caused
by severe acute
respiratory syndrome
coronavirus &
continues to progress.
While the world awaits
the distribution of
effective vaccines, a
number of
pharmacologic agents
have been studied for
treatment of
coronavirus disease
2019.
Remdesivir, a
nucleotide analogue
prodrug with in vitro
effects against a broad
array of RNA viruses,
has received
considerable attention
and that such: FDA
approved the use of
Remdesivir.
The World Health
Organization (WHO)
recommended against
the use of remdesivir
based on results from
the Solidarity trial.
In addition to
uncertainty about
efficacy, there are
concerns that the
demand for
remdesivir will
outpace supply.
24. 24
Rationale and Objective
The UK-based RECOVERY trial showed that dexamethasone administration compared
with placebo led to a significant reduction in mortality rate.
Trials examining the benefit of different corticosteroids were stopped early after
the results of RECOVERY led to corticosteroids being considered the standard of care.
Whether there is additional benefit from using both remdesivir and corticosteroids
requires further evaluation.
We used time-dependent propensity score matching to examine the association of
remdesivir administration with clinical improvement in patients admitted to our 5-
hospital health system from March 4 through August 29, 2020.
The aim of study is to evaluate TIME TO CLINICAL IMPROVEMENT of Remdesivir vs Non
in hospitalized patient who infected with Covid-19. and also its combination along with
Corticosteroid therapy.
26. Study Design
Multicenter (conducted 5 hospitals)
This study was conducted according to the International Society for Pharmacoeconomics
and Outcomes Research (ISPOR) reporting guideline for comparative effectiveness research.
Cohort (Retrospective)
1:1
Randomized clinical trial
Electronic Health Record
26
An electronic health record (EHR) is a digital version of a patient’s
paper chart. EHRs are real-time, patient-centered records that make
information available instantly and securely to authorized users.
29. 29
Primary Outcome
Time to clinical improvement from
the initiation of Remdesivir
Discharge alive from hospital
without any complication
Decrease 2 points in WHO severity
score
Secondary Outcome
Time to death from first
Remdesivir treatment
Time to clinical improvement after
initiation of Remdesivir + CS
Time to death after initiation of
Remdesivir + CS
Censored reports:
Failure of clinical improvement
at the last day of follow up.
Death at 28 days.
Patients who were discharged
alive at 28 days to account for
death and discharge being
competing risks.
30. 30
Statistical Analysis
• Gender
• Race
• DNI/DNR
• Oxygen devices
• Past Diagnosis
• Carlson Comorbidity Index
• Concomitant medications
Categorical data
(presented by %)
• Age
• BMI
• Vital sign
• Laboratory Result
Continues data
(presented by means ±SD)
Data presentation: Tabulated
31. Statistical Analysis (Cont’d)
Categorical
Data
• Log-rank test
• Kaplan-Meier
Continuous
Data
• Cox proportional hazards regression
31
They compared outcomes among patients who received corticosteroids plus remdesivir to patients who received remdesivir
alone.
Because the sample sizes for the 2 groups were similar and exposure to corticosteroids was time variant, marginal structural Cox
proportional hazards regression models were used to adjust for the nonrandomized administration of corticosteroids and to
analyze the association of corticosteroids with outcomes of interest in patients who had exposure to remdesivir.
The same set of time-dependent and time-invariant covariates were included in the model.
The inverse probability treatment weighting method was applied for parameter estimation.
32. 32
Method
Patients admitted to
JHHS (March 4- August
29)
Control patients
Admitted after April 27
Admitted before April
27
Received at least one
treatment of
Remdesivir
Treatment patient
Excluded Involved in
clinical trial
Excluded Still on
treatment at the time of
analysis
Exclusion
(Death/Discharge)
within 24 hr after
admission
1:1 Time-dependent propensity score matching
Propensity score–matched patients included in analyses on efficacy of remdesivir
Treatment patients removed
No match
Patients in study
33. Trial Regimen
A time constraint was
imposed so that a patient in
the remdesivir group with k
days of treatment, was
forced to match a patient in
the control group who
stayed at least k days (5
days maximum) in the
hospital since the matched
day
A patient who first
received remdesivir at a
given day t of
hospitalization was
matched with those
who did not, based on
their propensity scores
(hazard components) at
day t.
Patients were included
in the matching process
only if their admission
dates were later than
the earliest admission
date (April 27, 2020) of
patients in the
remdesivir group.
Propensity score at a
given hospitalization
day is the hazard of
exposure to
remdesivir treatment
on that day
Propensity scores were
calculated from a time
dependent Cox
proportional hazards
regression model using
the time to first receipt
of remdesivir as the
outcome.
33
34. Sensitivity Analysis
The analyses were repeated using the same propensity score–matching method but with
the following conditions:
Excluding remdesivir-
treated patients who also
received corticosteroids
Applying the ACTT-111
inclusion/exclusion criteria
to select qualified patients
for matching
Decreasing the number of days
that matched controls had to
remain in the hospital after the
matched day from a maximum
of 5 days to either 4 or 3 days.
Categorizing clinical
improvement using a 1-
point decrease in WHO
severity score instead of a
2-point decrease.
34
35. Reasons Of Discontinuation
Increased levels of liver enzyme above 200 U/L
Nausea
Epistaxis and tachycardia
Neck and mouth itching
Transition to comfort care
Bilirubin levels above 2mg/Dl
Estimated glomerular filtration rate less than 30 mL/min/1.73m2
35
36. 303 patients received 5 days course
33 patients did not complete 5 days
of treatment
6 patients received more than 5 days
Study flow
36
Patients admitted to
JHHS
(2483)
Control patients
(1957)
Admitted after April 27
(1117)
Admitted before April
27
(840)
Received at least 1
treatment of
Remdesivir
(358)
Treatment patient
(Received Remdesivir)
(342)
Excluded Involved in
clinical trial
(12)
Excluded Still on
treatment at the time
of analysis
(4)
Exclusion
(Death/Discharge) within
24 hr after admission
(168)
1:1 Time-dependent propensity score matching
Propensity score–matched patients included in analyses on efficacy of remdesivir
(570)
Treatment patients removed
No match
(57)
6 months period
From March 4 till August 30
Patients in study
(2315)
Total Number of Exclusion: 184
The median age:
60 years
Women: 153
Men: 189
Patient who stopped treatment early:
2.9%
The median time from admission to
treatment initiation was 1.1 days
37. Patient Characteristics
The characteristics of the patients and
therapies for remdesivir and Covid-19
were well balanced between the trial
groups at baseline.
According to the numbers, the
characteristics are somehow close, so
we can conclude that: There is no
significant difference that will
interfere with the results.
37
38. Primary Efficacy Outcomes
38
From 570 patients matched (285 Remdesivir
and 285 control)
• Median time for Remdesivir: 5 days
• Median time for control: 7 days
Primary Efficacy Outcome
Remdesivir group 236 (82.8%)
Control group 213 (74.4%)
95% CI 1.47 (1.22 – 1.79)
In Cox proportional hazards regression
models, Remdesivir treatment was
associated with significantly shortened
time to clinical improvement.
39. Primary Efficacy Outcomes
Patients treated with remdesivir and breathing
ambient air or nasal cannula oxygen reached clinical
improvement faster than matched controls, 5 days
vs 6 days (95% CI: 1.41 (1.12 – 1.79 )).
Those with severe disease (requiring higher levels of
respiratory support) also benefitted in the time to
clinical improvement from remdesivir treatment, 8
days vs 9 days (95%CI, 1.59 (1.02 - 2.49 )).
39
Primary Efficacy Outcome ACTT-1 (days)
Remdesivir group 5
Control group 6
95% CI 1.42 (1.15 – 1.72 )
Remdesivir administration was associated with
shortened time to clinical improvement
40. Secondary Efficacy Outcomes
Time To Death
Remdesivir group 22 deaths (7.7%)
Control group 40 deaths (14%)
95% CI 0.70 (0.38 – 1.28 )
This difference was not
statistically significant in the
time-to-death Analysis.
Mortality rate
Remdesivir group 16 deaths (6.3%)
Control group 33 deaths (13.1%)
95% CI 0.51 (0.25 – 1.04 )
This difference was not
statistically significant
40
41. Secondary Efficacy Outcomes
Time To Death Days
Remdesivir group 8.6
Control group 8.2
95% CI
Mild- Moderate:
0.27 (0.06 – 1.27 )
Severe:
0.78 (0.33 – 1.84 )
There was no significant mortality
benefit associated with remdesivir
treatment
41
Time To Death Days
Remdesivir group 9.1
Control group 9.6
42. 42
Sensitivity Analysis
And If the required period of hospitalization was lowered to 3 days or less
95%CI: 1.07 (0.89-1.28)
Remdesivir administration was still associated with a significant decrease in the time to
clinical improvement if the requirement was reduced to 4 days
95%CI:1.25 (1.03 - 1.50 )
The results were sensitive to the requirement that controls be selected from among patients
who remained hospitalized for the same duration of treatment as their matched counterpart.
43. 43
Combination therapy was associated with longer time
to clinical improvement (95%CI: 0.77 (0.62-0.97)).
The median time to death was increased for patients
who received combination therapy (15 days)
compared with remdesivir alone (6.5 days).
A marginal structural Cox proportional hazards
regression model did not show a significant reduction
in the hazard of death for patients who received
remdesivir and corticosteroids compared with
remdesivir alone (95%CI:1.94 (0.67-5.57)).
The sample sizes were too small to evaluate whether
combined therapy was associated with benefits for
patients with severe disease.
If the analysis was restricted to only patients who
received dexamethasone as the corticosteroid, the
combination of dexamethasone and remdesivir was not
associated with reduced mortality compared with
remdesivir alone. (95%CI:1.47 (0.46-4.67)).
44. 44
Discussion
Optimal implementation
of therapeutics to
decrease COVID-19
morbidity and mortality
is a global priority.
Remdesivir alone does not have a
robust mortality benefit for
patients with COVID-19,
remdesivir may still have an
important role to play in reducing
duration and severity of illness.
The mortality rate was
lower in the remdesivir
group, but the results
were not statistically
significant.
Finding showed that
Initiation of Remdesivir
is recommended for 5
days treatment courses.
There was no significant
reduction in the hazard
of death for patients
who received both
remdesivir and
corticosteroids.
The RECOVERY trial showed that
only patients receiving
supplemental oxygen or
additional respiratory support
benefitted from dexamethasone,
whereas patients breathing
ambient air did not.
The combination of
corticosteroids and
remdesivir in specific target
populations and the timing
of co-administration warrant
additional study.
45. 45
Authors Name Objective Result
Eun-Jeong Joo
Jae-Hoon Ko
Seong Eun Kim
Seung-Ji Kang
Ji Hyeon Baek
Eun Young Heo
Hye Jin Shi
Study was conducted to evaluate the
effect of remdesivir on clinical and
virology outcomes of severe COVID-19
patients from June to July 2020 in Korea.
The proportions of clinical recovery of the
remdesivir and supportive care group at
HD 14 and HD 28 were not statistically
different.
The proportion of patients requiring MV
support by HD 28 was significantly lower in
the remdesivir group than in the
supportive care group (22.9% vs.
44.7%, P = 0.032)
MV duration was significantly shorter in
the remdesivir group (average, 1.97 vs.
5.37 days; P = 0.017).
Jason D. Goldman
David C.B. Lye
David S. Hui
Kristen M. Marks
Raffaele Bruno
Rocio Montejano
Christoph D. Spinner
Massimo Galli
Study was conducted to monitor the
efficacy of Remdesivir in severely ill
patient (saO: <94%) for either 5 days or
10 days
Patients in the 10-day group had a
distribution in clinical status at day 14 that
was similar to that among patients in the 5-
day group (P=0.14).
In patients with severe Covid-19 not
requiring mechanical ventilation, our trial
did not show a significant difference
between a 5-day course and a 10-day
course of remdesivir.
46. Limitations Of Study
46
There could be unmeasured
variables that biased our treatment
effect estimates.
It is possible that there was a secular
trend in the quality of COVID-19 patient
care as our health system gained
experience
This protocol is consistent with ACTT-1,
which excluded patients expected to be
discharged from the hospital within 3
days of randomization
There was a trend toward a reduction in
mortality associated with remdesivir
administration that was similar in
magnitude to that shown in ACTT-1.
• Thus, we limited our matched
control group to the period
when remdesivir was
available
• The matching assignment is
therefore unlikely to bias the
results toward the null
hypothesis.
• Neither study result reached
statistical significance.
47. Strengths Of Study
Mentioning
the study
limitations
The rate of use
of guideline-
based
pharmacologic
therapy was
high and was
maintained
throughout
the trial.
The authors
were
reputable and
had previous
related
articles.
End points
were parallel
to the
objective.
Correlation
with other
studies.
47
48. 48
Conclusion
Remdesivir was associated with a significant decrease in the time to clinical recovery among
patients admitted to the hospital for treatment of COVID-19.
These results provide further evidence that remdesivir may be effective in reducing the
duration of COVID-19 illness, that a 5-day treatment course may be sufficient, and that patients
with milder disease likely benefit most.
The inclusion of a larger proportion of patients from underrepresented minority groups
provides much-needed evidence suggesting the effectiveness of remdesivir administration in
these groups.
The combination of remdesivir and corticosteroids was not associated with reduced mortality,
suggesting that additional studies assessing patients with COVID-19 are warranted.
49. 49
References Evaluation
34 references were used.
Ranged from 2000 to 2021
All references are related the to topic
discussed.
Most of the references are from 2020
All references are accessible.
The authors did not mention them-
selves in the references leaving the
chances for any other point of view.
50. Other Related Article
Objective
Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of
combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known.
Method
We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized
adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo
(control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15.
Result
A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients
receiving baricitinib had a median time to recovery of 7 days, as compared with 8 days with control (rate ratio for recovery,
1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15. Patients receiving high-
flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18
days with control. The 28-day mortality was 5.1% in the combination group and 7.8% in the control group. Serious adverse
events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage
points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to
-1.9; P = 0.003).
Conclusion
Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating
improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or
noninvasive ventilation. The combination was associated with fewer serious adverse events.
50 https://pubmed.ncbi.nlm.nih.gov/33306283/
Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19
51. For more information:
Zeinab Noormonavar
11630890@students.liu.edu.lb
Other Related Articles:
o https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919885/
Beneficial effect of combinational methylprednisolone and
remdesivir in hamster model of SARS-CoV-2 infection
o https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646058/
A comparative analysis of remdesivir and other repurposed
antivirals against SARS‐CoV‐2
51
