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The efficacy and safety of monoclonal antibody treatments against COVID-19: A systematic review and meta-analysis of randomized clinical trials

Ifan Ali Wafa1, Nando Reza Pratama1, David Setyo Budi1, Henry Sutanto2, Henry Sutanto3, Alfian Nur Rosyid1, Citrawati Dyah Kencono Wungu1 •
Airlangga University1, State University of New York System2, Maastricht University3
07 Jun 2021-medRxiv (Cold Spring Harbor Laboratory Press)-
TL;DR: In this article, the authors evaluated the efficacy and safety profile of monoclonal antibodies in COVID-19 patients and found that tocilizumab improved hospital discharge and reduced mortality as well as the need for mechanical ventilation.
Abstract: Objectives The use of monoclonal antibody for COVID-19 showed conflicting results in prior studies and its efficacy remains unclear. We aimed to comprehensively determine the efficacy and safety profile of monoclonal antibodies in COVID-19 patients. Methods Sixteen RCTs were analyzed using RevMan 5.4 to measure the pooled estimates of risk ratios (RRs) and standardized mean differences (SMDs) with 95% CIs. Results The pooled effect of monoclonal antibodies demonstrated mortality risk reduction (RR=0.89 (95%CI 0.82-0.96), I2=13%, fixed-effect). Individually, tocilizumab reduced mortality risk in severe to critical disease (RR=0.90 (95%CI 0.83-0.97), I2=12%, fixed-effect)) and lowered mechanical ventilation requirements (RR=0.76 (95%CI 0.62-0.94), I2=42%, random-effects). Moreover, it facilitated hospital discharge (RR=1.07 (95%CI 1.00-1.14), I2=60%, random-effects). Meanwhile, bamlanivimab-etesevimab and REGN-COV2 decrease viral load ((SMD=-0.33 (95%CI -0.59 to -0.08); (SMD=-3.39 (95%CI -3.82 to -2.97)). Interestingly, monoclonal antibodies did not improve hospital discharge at day 28-30 (RR=1.05 (95%CI 0.99–1.12), I2=71%, random-effects) and they displayed similar safety profile with placebo/standard therapy (RR=1.04 (95%CI 0.76-1.43), I2=54%, random-effects). Conclusion Tocilizumab improved hospital discharge and reduced mortality as well as the need for mechanical ventilation, while bamlanivimab-etesevimab and REGN-COV2 reduced viral load in mild to moderate outpatients. In general, monoclonal antibodies are safe and should be considered in severe to critical COVID-19 patients. Registration PROSPERO (CRD42021235112)

Summary (3 min read)

Jump to: [INTRODUCTION] – [Search Strategy] – [Data Collection] – [Data Extraction and Quality Assessment] – [Statistical Analysis] – [Study characteristics] – [MORTALITY All-cause mortality] – [Tocilizumab in severe-critical COVID-19] – [Sarilumab in severe-critical COVID-19] – [THE NEED FOR MECHANICAL VENTILATION] – [HOSPITAL DISCHARGE AT DAY 28-30] – [SERIOUS ADVERSE EVENTS] – [DISCUSSION] – [ANTI-IL-6R] – [ANTI-SPIKE-PROTEIN] – [ANTI-C5a] – [LIMITATION] and [CONCLUSION]

INTRODUCTION

  • A previous study reported that the SARS-CoV-2 S2 protein was important for viral entry and thought to be a potential target for neutralizing antibody (Walls et al., 2020) .
  • Moreover, at present, the application of monoclonal antibody as a therapeutic agent in COVID-19 shows conflicting results in prior studies, demanding further investigations.

Search Strategy

  • The PubMed , ScienceDirect, Cochrane Library, Proquest and Springer databases were systematically searched from January 25 until February 5, 2021, without any limitation of publication year.
  • The authors also performed manual searches, extended from February 5 to March 5, 2021, through MedRxiv and citation searching to get evidence from unpublished data and retrieve potential articles without missing any additional eligible studies.

Data Collection

  • The title and abstract of the articles were screened by IAW and NRP.
  • Duplications were removed using the Mendeley reference manager.

Data Extraction and Quality Assessment

  • IAW, NRP, and DSB independently extracted relevant data using the standardized form.
  • The following information was extracted: first author's name and publication year, study design, country, sample size, age, disease severity, dosage and administration of monoclonal antibodies, types of comparison, and outcomes (all-cause mortality, need for mechanical ventilation, hospital discharge at day 28-30, change of viral load, and serious adverse events).
  • The studies were classified into "low risk of bias," "some concerns," or "high risk of bias" according to the Cochrane risk of bias tool for randomized trial (RoB ver.
  • Any discrepancies were consulted with an expert and resolved by discussion until reaching consensus.
  • The Grading of Recommendation Assessment, Development, and Evaluation system was used to evaluate the quality of evidence of the findings (Brignardello-Petersen et al., 2018; Puhan et al., 2014) .

Statistical Analysis

  • Primary analyses were carried out using the Review Manager version 5.4 (The Cochrane Collaboration).
  • Pooled risk ratios (RRs) for dichotomous outcomes were evaluated using Mantel-Haenszel method.
  • If the value of I² statistics was <50% or the p-value was >0.1, the fixed-effects model could be applied; otherwise, the random-effects model would be used.
  • Subgroup analyses were done on monoclonal antibody types and disease severity for mortality risk, and monoclonal antibody types for the other outcomes.
  • Leave-one-out sensitivity analysis was conducted to find the source of statistical heterogeneity and demonstrate how each study affected the overall result.

Study characteristics

  • The authors identified 6032 and 7310 studies through primary database and manual searching, respectively.
  • After duplication removal, the authors screened potentially relevant studies and obtained 228 studies to be checked for eligibility.
  • Some studies were excluded due to the reasons documented in PRISMA diagram .
  • Among 16 RCTs, the REMAP-CAP trial (Gordon et al., 2021) was split into two separate intervention groups: the tocilizumab and sarilumab groups.
  • The characteristics and outcomes summary for each study, RoB ver.2 assessment, and the certainty of evidence of findings reported using GRADE system are presented in Supplementary Tables.

MORTALITY All-cause mortality

  • All-cause mortality was examined from 16 RCTs with a total of 8857 patients.
  • Subsequently, subgroup analyses on the disease severity and monoclonal antibody types were conducted, however only tocilizumab and sarilumab therapies for severe-critical COVID-19 patients were pooled, due to limited studies available .

Tocilizumab in severe-critical COVID-19

  • Meanwhile, TOCIBRAS trial mainly contributed to the statistical heterogeneity.
  • At last, Funnel plot and Egger's test did not show any publication bias.

Sarilumab in severe-critical COVID-19

  • Numerically, the RR was lower than that of tocilizumab, but it did not reach statistical significance.
  • Egger's test cannot be performed because there were only two studies included in the analysis.

THE NEED FOR MECHANICAL VENTILATION

  • Ten RCTs consisted of 6061 patients were examined .
  • Only studies involving anti-IL-6R antibodies reported mechanical ventilation outcome.
  • All participants were in severecritical disease, except for the participants from COVINTOC trial who were in moderatesevere state.
  • The authors also found that EMPACTA trial was the source of heterogeneity in the tocilizumab subgroup.

HOSPITAL DISCHARGE AT DAY 28-30

  • Eleven RCTs consisted of 7490 patients were examined .
  • Patients in tocilizumab and sarilumab subgroups had severe-critical disease, while patients receiving spike-protein antibodies were in moderate-severe COVID-19.
  • The p-value in 4 significant figures was 0.0498, therefore it reached statistical significance.
  • The funnel plot and Egger's test did not indicate any publication bias.

SERIOUS ADVERSE EVENTS

  • Interestingly, the CORIMUNO-TOCI 1 trial reported that tocilizumab was significantly safer than placebo/standard therapy.
  • These two studies were the main sources of heterogeneity in their analysis, although removing those studies from the tocilizumab subgroup did not change the direction of effect and statistical significance (RR=1.00 (95%CI 0.80-1.24), I 2 =0%, fixed-effects).
  • Publication bias was indicated in the anti-spike-protein subgroup.

DISCUSSION

  • The authors analyses showed that monoclonal antibodies provided benefits on mortality rate reduction, mostly because of the weight of tocilizumab studies.
  • Subgroup analysis demonstrated that tocilizumab had a significantly higher hospital discharge rate, but sarilumab and bamlanivimab did not.
  • Meanwhile, bamlanivimab-etesevimab and REGN-COV2 reported significant viral load reduction, but each was evaluated only from one RCT, therefore the authors cannot evaluate the pooled effect.
  • The authors analyses showed that monoclonal antibodies did not show significant harm or benefit as compared to placebo/standard care.
  • Not all studies included in this meta-analysis specified the number of treatment-related severe adverse events.

ANTI-IL-6R

  • The efficacy of tocilizumab was mostly reported in studies where the participants received corticosteroids, for example in RECOVERY and REMAP-CAP trials.
  • This highlights the potential benefit of the combination of tocilizumab and corticosteroids in mortality risk reduction.
  • It might have diminished the differences between the investigational drug and the control group.
  • In general, healthcare providers need to consider patients with severe COVID-19 to attain the maximum benefit from the inhibition of IL-6.

ANTI-SPIKE-PROTEIN

  • Gottlieb et al. (2021) reported that only bamlanivimab 2800mg showed a higher viral load reduction although it was statistically insignificant, while Chen et al. (2020) reported that bamlanivimab 2800mg significantly reduced viral load.
  • Besides, the natural course of the disease also plays a role in viral load reduction.
  • This may mask the clinical significance of neutralizing antibody administration.
  • It is important to mention that missing data from Gottlieb et al. (2020) was replaced using an approach detailed in Supplementary Materials.

ANTI-C5a

  • At present, there was only one study investigating anti-C5a with two outcomes included in this meta-analysis: the all-cause mortality and safety profile of the monoclonal antibody therapy.
  • The mortality rate in anti-C5a antibody IFX-1 group vs. placebo was numerically lower, 13.3% vs 26.7%, respectively.
  • This finding did not reach statistical significance, probably owing to the small number of participants.
  • Additionally, compared to placebo/standard care, neither benefit nor harm was observed.

LIMITATION

  • This meta-analysis has several limitations: (1) some studies were open-labelled; thus, the risk of bias regarding allocation concealment in those studies could not be ruled out; (2) We mainly discussed IL-6R inhibitors (e.g., tocilizumab) because most published RCTs are tocilizumab-associated studies and existing studies on other antibodies are scarce.the authors.the authors.
  • (3) The small number of participants in some studies may increase the likelihood of type II statistical error.
  • Larger scale RCTs are required to confirm the findings; (4) many other trials are ongoing; therefore, this study needs to be updated as soon as more trials become available.
  • Nevertheless, this meta-analysis provides a solid evidence by incorporating only RCTs.
  • To the best of their knowledge, this is the first meta-analysis that investigated the efficacy and safety of various monoclonal antibodies on clinical and laboratory outcomes, as well as their safety profile in patients with COVID-19.

CONCLUSION

  • In conclusion, monoclonal antibody is beneficial in reducing mortality risk and the need for mechanical ventilation, but not hospital discharge in COVID-19 patients.
  • In contrast to sarilumab, tocilizumab reduces mortality risk in severe to critical patients, reduces the need for mechanical ventilation, and increases hospital discharge at day 28-30.
  • Bamlanivimab monotherapy does not reduce mortality, increase hospital discharge, nor reduce viral load; while bamlanivimab-etesevimab and REGN-COV2 significantly decrease viral load.
  • IFX-1 shows no benefit in mortality risk reduction.
  • No major safety concern was documented for all the monoclonal antibodies.

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Figures (6)

Content maybe subject to copyright    Report

1
The efficacy and safety of monoclonal antibody treatments against COVID-19: A
1
systematic review and meta-analysis of randomized clinical trials
2
3
Ifan Ali Wafa
a
, Nando Reza Pratama
a
, David Setyo Budi
a
, Henry Sutanto
b,c
, Alfian Nur
4
Rosyid
d
, Citrawati Dyah Kencono Wungu
e,f,
*
5
6
7
8
a
Faculty of Medicine, Universitas Airlangga, Indonesia
9
b
Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht
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University, The Netherlands
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c
Department of Physiology and Biophysics, State University of New York (SUNY)
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Downstate Health Sciences University, New York, USA
13
d
Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas
14
Airlangga, Indonesia
15
e
Department of Physiology and Medical Biochemistry, Faculty of Medicine, Universitas
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Airlangga, Indonesia
17
f
Institute of Tropical Disease, Universitas Airlangga, Indonesia
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19
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21
22
23
Word Count: 3480 words (excluding abstract and references)
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25
26
27
28
Correspondence:
29
Citrawati Dyah Kencono Wungu, MD., PhD.
30
Department of Physiology and Medical Biochemistry, Airlangga University
31
Jalan Mayjen Prof. Dr. Moestopo No.47, Surabaya, Indonesia
32
Email:
citrawati.dyah@fk.unair.ac.id
33
34
. CC-BY-NC 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.04.21258343doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
2
Abstract
35
Objectives: The use of monoclonal antibody for COVID-19 showed conflicting results in
36
prior studies and its efficacy remains unclear. We aimed to comprehensively
37
determine the efficacy and safety profile of monoclonal antibodies in COVID-
38
19 patients.
39
Methods: Sixteen RCTs were analyzed using RevMan 5.4 to measure the pooled
40
estimates of risk ratios (RRs) and standardized mean differences (SMDs) with
41
95% CIs.
42
Results: The pooled effect of monoclonal antibodies demonstrated mortality risk
43
reduction (RR=0.89 (95%CI 0.82-0.96), I
2
=13%, fixed-effect). Individually,
44
tocilizumab reduced mortality risk in severe to critical disease (RR=0.90
45
(95%CI 0.83-0.97), I
2
=12%, fixed-effect)) and lowered mechanical ventilation
46
requirements (RR=0.76 (95%CI 0.62-0.94), I
2
=42%, random-effects).
47
Moreover, it facilitated hospital discharge (RR=1.07 (95%CI 1.00-1.14),
48
I
2
=60%, random-effects). Meanwhile, bamlanivimab-etesevimab and REGN-
49
COV2 decrease viral load ((SMD=-0.33 (95%CI -0.59 to
50
-0.08); (SMD=-3.39 (95%CI -3.82 to -2.97)). Interestingly, monoclonal
51
antibodies did not improve hospital discharge at day 28-30 (RR=1.05 (95%CI
52
0.99–1.12), I
2
=71%, random-effects) and they displayed similar safety profile
53
with placebo/standard therapy (RR=1.04 (95%CI 0.76-1.43), I
2
=54%, random-
54
effects).
55
Conclusion: Tocilizumab improved hospital discharge and reduced mortality as well as the
56
need for mechanical ventilation, while bamlanivimab-etesevimab and REGN-
57
COV2 reduced viral load in mild to moderate outpatients. In general,
58
monoclonal antibodies are safe and should be considered in severe to critical
59
COVID-19 patients.
60
Keywords: COVID-19; Monoclonal Antibody; Mortality; Viral load; Meta-analysis
61
Registration: PROSPERO (CRD42021235112)
62
. CC-BY-NC 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.04.21258343doi: medRxiv preprint
3
INTRODUCTION
63
Since December 2019, a novel coronavirus disease (COVID-19) firstly discovered in
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Wuhan, China has spread globally and profoundly affected various aspects of life (Li et al.,
65
2020). The viral infectious disease is caused by SARS-CoV-2; an enveloped, positive-sense,
66
single-stranded genomic ribonucleic acid (+ssRNA) virus from the group of Betacoronavirus
67
in the family of Coronaviridae (Hu et al., 2021). In the lungs, SARS-CoV-2 binds to
68
angiotensin converting enzyme type-2 (ACE-2) receptors at the membrane of pulmonary
69
alveolar cells type-2 and undergoes endocytosis. Subsequently, the interaction of viral
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antigen with RIG-I-like receptors (RLRs) activates the host immune system as an effort to
71
eliminate the virus from the body (Hertanto et al., 2021), predisposing to the clinical
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presentations of COVID-19 patients, ranging from asymptomatic or mild up to severe disease
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state with pneumonia and acute respiratory distress syndrome that can ultimately lead to
74
death (Lai et al., 2020).
75
The development of optimal and effective therapies for COVID-19 is essential to
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minimize COVID-19 morbidity and mortality (Lu, 2020; Li and De Clercq, 2020). Several
77
components of the virus and host immune system have been identified as potential targets in
78
COVID-19 management. A previous study reported that the SARS-CoV-2 S2 protein was
79
important for viral entry and thought to be a potential target for neutralizing antibody (Walls
80
et al., 2020). Moreover, the SARS-CoV-2 infection could trigger a hyperactive immune
81
response, leading to cytokine release syndrome (CRS) or cytokine storm (Hertanto et al.,
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2021). Among numerous proinflammatory cytokines involved in CRS, interleukin (IL)-6 is
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one of the most critical and has been associated with a poor prognosis (Zhang et al., 2020a;
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Zhang et al., 2020b; Zhao, 2020). Therefore, the inhibition of IL-6 (e.g., by preventing the
85
binding to its receptors) could prevent the occurrence of CRS and lower the severity of the
86
disease. Moreover, complement C5a and white blood cells (i.e., neutrophil and monocytes)
87
were detected in the bronchoalveolar lavage fluid (BALF) of COVID-19 patients, supporting
88
the chemoattraction role of C5a in lungs-derived C5aR1-expressing cells; which is
89
responsible for cell damage and ARDS (Carvelli et al., 2020). Of note, C5a is one of the
90
major drivers for complement-mediated inflammation that rapidly responds to pathogens and
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cellular injury (Woodruff and Shukla, 2020).
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Monoclonal antibody is one of the proposed therapeutic options for COVID-19. Anti-
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SARS-CoV-2 monoclonal antibodies are among the latest investigational COVID-19
94
treatments granted with emergency use authorization (EUA) from the United States Food and
95
. CC-BY-NC 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.04.21258343doi: medRxiv preprint
4
Drug Administration (FDA). Briefly, monoclonal antibodies recognize one epitope of an
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antigen while polyclonal antibodies recognize multiple epitopes (Lipman et al., 2005). The
97
variable region can be modified to target specific molecules, including the S2-protein,
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cytokines, and cytokine receptors. Among 5 Antibody isotypes—IgA (subclasses IgA1 and
99
IgA2), IgE, IgD, IgM, and IgG (subclasses IgG1, IgG2, IgG3 and IgG4) —IgG is commonly
100
selected for therapeutic purposes due to its strong binding affinity to an antigen and its Fc
101
receptor, supported by its long serum half-life (Chames et al., 2009; Lu, 2020). As the
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consequence, the administration of neutralizing monoclonal antibody targeting SARS-CoV-2
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spike proteins allows the inhibition of virus attachment to human ACE-2 receptors, thus
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inhibits viral entry (Tian et al., 2020). To prevent complement system activation triggered
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during SARS-CoV-2 infection, a recent study proposed the use of monoclonal antibody
106
against C5a (anti-C5a) (Woodruff and Shukla, 2020). Among available monoclonal
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antibodies for COVID-19, anti-IL-6 receptors and anti-SARS-CoV-2 are widely studied in
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clinical trials (Yang et al., 2020; Patel et al., 2021).
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Nonetheless, the efficacy and safety of this pharmacological agent remain
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controversial (FDA, 2020; Patel et al., 2021). Moreover, at present, the application of
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monoclonal antibody as a therapeutic agent in COVID-19 shows conflicting results in prior
112
studies, demanding further investigations. Thus, this meta-analysis aims to assess the
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previously reported efficacy and safety of monoclonal antibodies on clinical and laboratory
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outcomes and its safety profile in COVID-19 patients.
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MATERIALS AND METHODS
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Search Strategy
118
The PubMed (MEDLINE), ScienceDirect, Cochrane Library, Proquest and Springer
119
databases were systematically searched from January 25 until February 5, 2021, without any
120
limitation of publication year. We also performed manual searches, extended from February 5
121
to March 5, 2021, through MedRxiv and citation searching to get evidence from unpublished
122
data and retrieve potential articles without missing any additional eligible studies. The
123
following keywords were used: “(COVID-19) AND ((Monoclonal Antibody) OR
124
(Neutralizing Antibody) OR (Serotherapy)) AND ((Viral Load) OR (Oxygen) OR (Duration)
125
OR (Mortality) OR (Inflammation))”. Additional details about the search strategy are
126
available in Supplementary Materials.
127
. CC-BY-NC 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.04.21258343doi: medRxiv preprint
5
Data Collection
128
The title and abstract of the articles were screened by IAW and NRP. Duplications
129
were removed using the Mendeley reference manager. We independently screened the title
130
and abstract of all retrieved studies based on the following eligibility criteria: (1) participants
131
confirmed at any clinical stage of COVID-19 with/without other comorbidities; (2) adult (
≥
18
132
years) male/female study population; (3) the study involved monoclonal antibody treatments
133
of interest; (4) the study compared the intervention group with control (placebo or/and
134
standard of care or combination therapy); (5) the study evaluated efficacy (i.e. mortality, need
135
for mechanical ventilation, hospital discharge, virologic outcomes) or safety outcomes
136
(serious adverse events); (6) study type was randomized controlled trial (RCT).
137
Data Extraction and Quality Assessment
138
IAW, NRP, and DSB independently extracted relevant data using the standardized
139
form. The following information was extracted: first author’s name and publication year,
140
study design, country, sample size, age, disease severity, dosage and administration of
141
monoclonal antibodies, types of comparison, and outcomes (all-cause mortality, need for
142
mechanical ventilation, hospital discharge at day 28-30, change of viral load, and serious
143
adverse events). Serious adverse events were defined as any untoward medical occurrence
144
that are potentially related to monoclonal antibody treatment.
145
The studies were classified into “low risk of bias,” “some concerns,” or “high risk of
146
bias” according to the Cochrane risk of bias tool for randomized trial (RoB ver.2) (Sterne et
147
al., 2019). Any discrepancies were consulted with an expert and resolved by discussion until
148
reaching consensus. The Grading of Recommendation Assessment, Development, and
149
Evaluation (GRADE) system was used to evaluate the quality of evidence of the findings
150
(Brignardello-Petersen et al., 2018; Puhan et al., 2014).
151
Statistical Analysis
152
Primary analyses were carried out using the Review Manager version 5.4 (The
153
Cochrane Collaboration). Pooled risk ratios (RRs) for dichotomous outcomes were evaluated
154
using Mantel-Haenszel method. Standardized mean differences (SMDs) of continuous
155
outcomes were pooled using inverse variance. I
2
test was used to quantify heterogeneity
156
between studies, with values I
2
>50% represents moderate-to-high heterogeneity. If the value
157
of I² statistics was <50% or the p-value was >0.1, the fixed-effects model could be applied;
158
otherwise, the random-effects model would be used. Begg's funnel plot and Egger’s test were
159
. CC-BY-NC 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.04.21258343doi: medRxiv preprint
Citations
More filters
Journal Article•DOI•
Efficacy of tocilizumab in the treatment of COVID‐19: An umbrella review

[...]

Mohammad Mahdi Rezaei Tolzali, M Noori, Pourya Shokri, Shayan Rahmani, S Ali Khanzadeh, Seyed Aria Nejadghaderi, Asra Fazlollahi, Mark J.M. Sullman, Kuljit Singh, Ali-Asghar Kolahi, Shahnam Arshi, Saeid Safiri 
27 Aug 2022-Reviews in Medical Virology
TL;DR: Tocilizumab treatment reduced therisk of intubation, mortality and the length of hospital stay, without increasing the risk of superimposed infections in COVID‐19 patients.
Abstract: Tocilizumab is an interleukin (IL)‐6 receptor inhibitor that has been proposed as a therapeutic agent for treating coronavirus disease 2019 (COVID‐19). The aim of this umbrella review was to determine the efficacy of tocilizumab in treating COVID‐19, and to provide an overview of all systematic reviews on this topic. We systematically searched PubMed, Scopus, the Web of Science collection, the Cochrane library, Epistemonikos, and Google Scholar, as well as the medRxiv preprint server. These databases were searched up to 30 September 2021, using the following keywords: ‘SARS‐CoV‐2’, ‘COVID‐19’, ‘tocilizumab’, ‘RHPM‐1’, ‘systematic review’, and ‘meta‐analysis’. Studies were included if they were systematic reviews (with or without meta‐analysis) investigating the efficacy or safety of tocilizumab in confirmed COVID‐19 patients. The AMSTAR 2 checklist was used to assess quality of the included articles, while publication bias was examined using Egger's test. A total of 50 eligible systematic reviews were included. The pooled estimates showed significant reductions in clinical failure (risk ratio (RR) 0.75; 95% confidence interval (CI), 0.61–0.93), deaths (RR 0.78; 95%CI, 0.71–0.85) and the need for mechanical ventilation (RR 0.77; 95%CI, 0.64–0.92) for those receiving tocilizumab compared with the control group. Also, an emerging survival benefit was demonstrated for those who received tocilizumab, over those in the control group (adjusted hazard ratio (aHR) 0.52; 95%CI, 0.43–0.63). In addition, tocilizumab substantially increased the number of ventilator‐free days, compared with the control treatments (weighted mean difference (WMD) 3.38; 95%CI, 0.51–6.25). Furthermore, lymphocyte count (WMD 0.26 × 109/L; 95%CI, 0.14–0.37), IL‐6 (WMD 176.99 pg/mL; 95%CI, 76.34–277.64) and D‐dimer (WMD 741.08 ng/mL; 95%CI, 109.42–1372.75) were all significantly elevated in those receiving tocilizumab. However, the level of lactate dehydrogenase (LDH) (WMD −30.88 U/L; 95%CI, −51.52, −10.24) and C‐reactive protein (CRP) (WMD ‐104.83 mg/L; 95%CI, −133.21, −76.46) were both significantly lower after treatment with tocilizumab. Tocilizumab treatment reduced the risk of intubation, mortality and the length of hospital stay, without increasing the risk of superimposed infections in COVID‐19 patients. Therefore, tocilizumab can be considered an effective therapeutic agent for treating patients with COVID‐19.

3 citations

References
More filters
Journal Article•DOI•
Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia.

[...]

Carlos Salama1, Jian Han2, Linda Yau2, W. Reiss2, Benjamin Kramer2, Jeffrey D. Neidhart3, Gerard J. Criner4, Emma Kaplan-Lewis, Rachel Baden, Lavannya Pandit5, Miriam L Cameron6, Julia Garcia-Diaz7, Victoria Chávez, Martha Mekebeb-Reuter8, Ferdinando Lima de Menezes, Reena Shah9, Maria F. González-Lara, Beverly Assman2, Jamie Freedman2, Shalini V. Mohan2 •
Icahn School of Medicine at Mount Sinai1, Genentech2, San Juan College3, Temple University4, United States Department of Veterans Affairs5, Holy Cross Hospital6, Ochsner Health System7, Stellenbosch University8, Aga Khan University9
07 Jan 2021-The New England Journal of Medicine
TL;DR: In hospitalized patients with Covid-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival.
Abstract: Background Coronavirus disease 2019 (Covid-19) pneumonia is often associated with hyperinflammation. Despite the disproportionate incidence of Covid-19 among underserved and racial and eth...

986 citations

Journal Article•DOI•
Drug treatment options for the 2019-new coronavirus (2019-nCoV)

[...]

Hongzhou Lu1•
Fudan University1
28 Jan 2020-BioScience Trends
TL;DR: Three general methods, which include existing broad-spectrum antiviral drugs using standard assays, screening of a chemical library containing many existing compounds or databases, and the redevelopment of new specific drugs based on the genome and biophysical understanding of individual coronaviruses, are used to discover the potential antiviral treatment of human pathogen coronavirus.
Abstract: As of January 22, 2020, a total of 571 cases of the 2019-new coronavirus (2019-nCoV) have been reported in 25 provinces (districts and cities) in China. At present, there is no vaccine or antiviral treatment for human and animal coronavirus, so that identifying the drug treatment options as soon as possible is critical for the response to the 2019-nCoV outbreak. Three general methods, which include existing broad-spectrum antiviral drugs using standard assays, screening of a chemical library containing many existing compounds or databases, and the redevelopment of new specific drugs based on the genome and biophysical understanding of individual coronaviruses, are used to discover the potential antiviral treatment of human pathogen coronavirus. Lopinavir /Ritonavir, Nucleoside analogues, Neuraminidase inhibitors, Remdesivir, peptide (EK1), abidol, RNA synthesis inhibitors (such as TDF, 3TC), anti-inflammatory drugs (such as hormones and other molecules), Chinese traditional medicine, such ShuFengJieDu Capsules and Lianhuaqingwen Capsule, could be the drug treatment options for 2019-nCoV. However, the efficacy and safety of these drugs for 2019- nCoV still need to be further confirmed by clinical experiments.

911 citations

Journal Article•DOI•
Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): Facts and myths.

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Chih-Cheng Lai, Yen Hung Liu1, Cheng Yi Wang1, Ya-Hui Wang1, Shun Chung Hsueh2, Muh Yen Yen3, Wen Chien Ko4, Po-Ren Hsueh5 •
Fu Jen Catholic University1, Taipei Medical University2, National Yang-Ming University3, National Cheng Kung University4, National Taiwan University5
04 Mar 2020-Journal of Microbiology Immunology and Infection
TL;DR: The most common finding on chest imaging among patients with pneumonia was ground-glass opacity with bilateral involvement, and age and disease severity may be correlated with the outcomes of COVID-19.
Abstract: Since the emergence of coronavirus disease 2019 (COVID-19) (formerly known as the 2019 novel coronavirus [2019-nCoV]) in Wuhan, China in December 2019, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more than 75,000 cases have been reported in 32 countries/regions, resulting in more than 2000 deaths worldwide. Despite the fact that most COVID-19 cases and mortalities were reported in China, the WHO has declared this outbreak as the sixth public health emergency of international concern. The COVID-19 can present as an asymptomatic carrier state, acute respiratory disease, and pneumonia. Adults represent the population with the highest infection rate; however, neonates, children, and elderly patients can also be infected by SARS-CoV-2. In addition, nosocomial infection of hospitalized patients and healthcare workers, and viral transmission from asymptomatic carriers are possible. The most common finding on chest imaging among patients with pneumonia was ground-glass opacity with bilateral involvement. Severe cases are more likely to be older patients with underlying comorbidities compared to mild cases. Indeed, age and disease severity may be correlated with the outcomes of COVID-19. To date, effective treatment is lacking; however, clinical trials investigating the efficacy of several agents, including remdesivir and chloroquine, are underway in China. Currently, effective infection control intervention is the only way to prevent the spread of SARS-CoV-2.

759 citations

Journal Article•DOI•
Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial.

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Robert L. Gottlieb1, Ajay Nirula2, Peter Chen3, Joseph Boscia, Barry Heller4, Jason Morris, Gregory D. Huhn, Jose Cardona, Bharat Mocherla, Valentina Stosor5, Imad Shawa6, Princy Kumar7, Andrew C. Adams2, Jacob Van Naarden2, Kenneth L. Custer2, Michael Durante2, Gerard J. Oakley2, Andrew E. Schade2, Timothy R. Holzer2, Philip J. Ebert2, Richard E. Higgs2, Nicole L. Kallewaard2, Janelle Sabo2, Dipak R. Patel2, Paul Klekotka2, Lei Shen2, Daniel Skovronsky2 •
Baylor University Medical Center1, Eli Lilly and Company2, Cedars-Sinai Medical Center3, California State University, Long Beach4, Northwestern University5, Franciscan Health6, Georgetown University7
16 Feb 2021-JAMA
TL;DR: The BLAZE-1 trial as mentioned in this paper evaluated the effect of bamlanivimab monotherapy and combination therapy on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in mild to moderate COVID-19.
Abstract: Importance: Coronavirus disease 2019 (COVID-19) continues to spread rapidly worldwide. Neutralizing antibodies are a potential treatment for COVID-19. Objective: To determine the effect of bamlanivimab monotherapy and combination therapy with bamlanivimab and etesevimab on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in mild to moderate COVID-19. Design, Setting, and Participants: The BLAZE-1 study is a randomized phase 2/3 trial at 49 US centers including ambulatory patients (N = 613) who tested positive for SARS-CoV-2 infection and had 1 or more mild to moderate symptoms. Patients who received bamlanivimab monotherapy or placebo were enrolled first (June 17-August 21, 2020) followed by patients who received bamlanivimab and etesevimab or placebo (August 22-September 3). These are the final analyses and represent findings through October 6, 2020. Interventions: Patients were randomized to receive a single infusion of bamlanivimab (700 mg [n = 101], 2800 mg [n = 107], or 7000 mg [n = 101]), the combination treatment (2800 mg of bamlanivimab and 2800 mg of etesevimab [n = 112]), or placebo (n = 156). Main Outcomes and Measures: The primary end point was change in SARS-CoV-2 log viral load at day 11 (±4 days). Nine prespecified secondary outcome measures were evaluated with comparisons between each treatment group and placebo, and included 3 other measures of viral load, 5 on symptoms, and 1 measure of clinical outcome (the proportion of patients with a COVID-19-related hospitalization, an emergency department [ED] visit, or death at day 29). Results: Among the 577 patients who were randomized and received an infusion (mean age, 44.7 [SD, 15.7] years; 315 [54.6%] women), 533 (92.4%) completed the efficacy evaluation period (day 29). The change in log viral load from baseline at day 11 was -3.72 for 700 mg, -4.08 for 2800 mg, -3.49 for 7000 mg, -4.37 for combination treatment, and -3.80 for placebo. Compared with placebo, the differences in the change in log viral load at day 11 were 0.09 (95% CI, -0.35 to 0.52; P = .69) for 700 mg, -0.27 (95% CI, -0.71 to 0.16; P = .21) for 2800 mg, 0.31 (95% CI, -0.13 to 0.76; P = .16) for 7000 mg, and -0.57 (95% CI, -1.00 to -0.14; P = .01) for combination treatment. Among the secondary outcome measures, differences between each treatment group vs the placebo group were statistically significant for 10 of 84 end points. The proportion of patients with COVID-19-related hospitalizations or ED visits was 5.8% (9 events) for placebo, 1.0% (1 event) for 700 mg, 1.9% (2 events) for 2800 mg, 2.0% (2 events) for 7000 mg, and 0.9% (1 event) for combination treatment. Immediate hypersensitivity reactions were reported in 9 patients (6 bamlanivimab, 2 combination treatment, and 1 placebo). No deaths occurred during the study treatment. Conclusions and Relevance: Among nonhospitalized patients with mild to moderate COVID-19 illness, treatment with bamlanivimab and etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; no significant difference in viral load reduction was observed for bamlanivimab monotherapy. Further ongoing clinical trials will focus on assessing the clinical benefit of antispike neutralizing antibodies in patients with COVID-19 as a primary end point. Trial Registration: ClinicalTrials.gov Identifier: NCT04427501.

714 citations

Journal Article•DOI•
Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia.

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Ivan O. Rosas1, Norbert Bräu2, Norbert Bräu3, Michael F. Waters, Ronaldo C. Go, Bradley D Hunter4, Sanjay Bhagani5, Daniel Skiest6, Mariam Aziz7, Nichola Cooper8, Ivor S. Douglas9, Sinisa Savic10, Taryn Youngstein8, Lorenzo Del Sorbo11, Antonio Cubillo Gracian, David J. De La Zerda12, Andrew Ustianowski, Min Bao13, Sophie Dimonaco14, Emily Graham14, Balpreet Matharu14, Helen Spotswood14, Larry Tsai13, Atul Malhotra15 •
Baylor College of Medicine1, Icahn School of Medicine at Mount Sinai2, Veterans Health Administration3, Primary Children's Hospital4, Royal Free Hospital5, University of Massachusetts Boston6, Rush University Medical Center7, Imperial College London8, University of Colorado Denver9, Leeds Teaching Hospitals NHS Trust10, University Health Network11, University of Miami12, Genentech13, Hoffmann-La Roche14, University of California, San Diego15
25 Feb 2021-The New England Journal of Medicine
TL;DR: In this paper, a randomized trial involving hospitalized patients with severe Covid-19 pneumonia, the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo at 28 days.
Abstract: Background Coronavirus disease 2019 (Covid-19) is associated with immune dysregulation and hyperinflammation, including elevated interleukin-6 levels. The use of tocilizumab, a monoclonal antibody against the interleukin-6 receptor, has resulted in better outcomes in patients with severe Covid-19 pneumonia in case reports and retrospective observational cohort studies. Data are needed from randomized, placebo-controlled trials. Methods In this phase 3 trial, we randomly assigned patients who were hospitalized with severe Covid-19 pneumonia in a 2:1 ratio receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight) or placebo. Approximately one quarter of the participants received a second dose of tocilizumab or placebo 8 to 24 hours after the first dose. The primary outcome was clinical status at day 28 on an ordinal scale ranging from 1 (discharged or ready for discharge) to 7 (death) in the modified intention-to-treat population, which included all the patients who had received at least one dose of tocilizumab or placebo. Results Of the 452 patients who underwent randomization, 438 (294 in the tocilizumab group and 144 in the placebo group) were included in the primary and secondary analyses. The median value for clinical status on the ordinal scale at day 28 was 1.0 (95% confidence interval [CI], 1.0 to 1.0) in the tocilizumab group and 2.0 (non-ICU hospitalization without supplemental oxygen) (95% CI, 1.0 to 4.0) in the placebo group (between-group difference, -1.0; 95% CI, -2.5 to 0; P = 0.31 by the van Elteren test). In the safety population, serious adverse events occurred in 103 of 295 patients (34.9%) in the tocilizumab group and in 55 of 143 patients (38.5%) in the placebo group. Mortality at day 28 was 19.7% in the tocilizumab group and 19.4% in the placebo group (weighted difference, 0.3 percentage points (95% CI, -7.6 to 8.2; nominal P = 0.94). Conclusions In this randomized trial involving hospitalized patients with severe Covid-19 pneumonia, the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo at 28 days. (Funded by F. Hoffmann-La Roche and the Department of Health and Human Services; COVACTA ClinicalTrials.gov number, NCT04320615.).

666 citations

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Use of Tocilizumab in COVID-19: A Systematic Review and Meta-Analysis of Current Evidence.

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