preproo - mosby · in december 2019, a novel coronavirus outbreak was reported from wuhan in the...

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Mayo Clinic Proceedings Treatment of COVID-19

© 2020 Mayo Foundation for Medical Education and Research. Mayo Clin Proc. 2020;95(x):xx-xx.

Treatment Considerations for COVID-19:

A Critical Review of the Evidence (or Lack Thereof)

Prakhar Vijayvargiya, MBBS1, Zerelda Esquer Garrigos, MD1, Natalia E. Castillo Almeida, MD1, Pooja R. Gurram, MBBS1, Ryan W. Stevens, PharmD2, Raymund R.

Razonable, MD1 1Division of Infectious Diseases, Department of Medicine,

Mayo Clinic College of Medicine and Science, Rochester, MN, USA2Department of Pharmacy Services

Mayo Clinic, Rochester, MN, USA

Financial support and conflict of interest disclosure: RRR serves as the principal

investigator on clinical trials for tocilizumab and sarilumab. None of the other authors

have any conflicts of interest that would influence the manuscript.

Correspondence:

Raymund R. Razonable, MD

Division of Infectious Diseases

Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

[email protected]

mailto:[email protected]

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Article Highlights

• Antiviral and immunomodulatory therapies, investigational and re-purposed, for

the management of Coronavirus Disease-2019 (COVID-19) are reviewed. The

use of these drugs should be under clinical trial protocols.

• The mechanisms of action for treatment options being considered for COVID-19,

and their potential toxicities, are discussed.

• A hypothetical protocol that may serve as a starting point for healthcare providers

to develop institution-specific protocols based on available resources.

ABSTRACT

The novel severe acute respiratory syndrome coronavirus 2 is causing a worldwide

pandemic that may lead to a highly morbid and potentially fatal coronavirus disease-19

(COVID-19). There is currently no drug that has been proven as an effective therapy for

COVID-19. Several candidate drugs are being considered and evaluated for treatment.

This includes clinically-available drugs, such as chloroquine, hydroxychloroquine, and

lopinavir/ritonavir, which are being repurposed for the treatment of COVID-19. Novel

experimental therapies, such as remdesivir and favipiravir, are also actively being

investigated for antiviral efficacy. Clinically-available and investigational

immunomodulators, such as the IL-6 inhibitors tocilizumab and sarilumab and the anti-

GMCSF lenzilumab, are being tested for their anticipated effect in counteracting the pro-

inflammatory cytokine environment that characterizes severe and critical COVID-19.

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This review article examines the evidence behind the potential use of these leading

drug candidates for the treatment of COVID-19. The authors conclude, based on this

review, that there is still no high-quality evidence to support any of these proposed drug

therapies. The authors, therefore, encourage the enrollment of eligible patients to

multiple ongoing clinical trials that assess the efficacy and safety of these candidate

therapies. Until the results of controlled trials are available, none of the suggested

therapeutics is clinically proven as an effective therapy for COVID-19.

Abbreviations

2019-nCoV = Novel coronavirus ACE2 = Angiotensin-converting enzyme 2 ARDS = Acute respiratory distress syndrome CC50 = 0% cytotoxic concentration COVID-19 = Coronavirus disease 2019 CRP = C-reactive protein EC50 = Half-maximal effective concentration FDA = Food and Drug Administration GM-CS F= Granulocyte-macrophage colony-stimulating factor HIV = Human immunodeficiency viruses IV = Intravenous IFN-α = Interferon-alpha IFN-β = Interferon-beta Il-6 = Interleukin 6 LPV = Lopinavir LPV/ = Lopinavir/ritonavir MERS-CoV = Middle East respiratory syndrome-related Coronavirus NS1 = Nonstructural protein 1 QTc = Corrected QT RCT = Randomized controlled trial SARS = Severe acute respiratory syndrome SARS-CoV = Severe acute respiratory syndrome coronavirus SARS-CoV-2 = Severe acute respiratory syndrome coronavirus 2 US = United States

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Introduction

In December 2019, a novel coronavirus outbreak was reported from Wuhan in

the Hubei province of China. As of April 16, 2020, the virus has infected over 2,090,000

people worldwide, resulting in over 139,000 deaths.1 Initially called novel coronavirus

(2019-nCoV), it was officially named severe acute respiratory syndrome coronavirus 2

(SARS-CoV-2) because of its similarities with the agent that caused severe acute

respiratory syndrome (SARS) outbreak in 2003.2 Severe acute respiratory syndrome

coronavirus (SARS-CoV), Middle East respiratory syndrome-related coronavirus

(MERS) and SARS-CoV-2 belong to the Genus betacoronavirus and are agents of

respiratory infections in humans.

The infection caused by SARS-CoV-2 manifests as Coronavirus disease 2019

(COVID-19). The majority of patients infected with SARS-CoV-2 either remain

asymptomatic or demonstrate mild symptoms and recover from their illness. The most

common clinical presentation is pneumonia with symptoms of fever, dry cough, and

shortness of breath.3 Anosmia, dysgeusia, and diarrhea have been reported.4 About 20-

30% of patients require intensive care for respiratory support, and over 15% of patients

with severe pneumonia develop acute respiratory distress syndrome (ARDS) (Figure

1).5, 6

There is currently no proven drug for the treatment of COVID-19. The standard of

care is supportive measure, aimed at managing fever, dehydration, and constitutional

and other clinical symptoms. Because of the morbid and potentially fatal nature of

COVID-19, there have been efforts to repurpose other clinically available drugs based

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upon antiviral activities that have either been demonstrated in vitro or proposed due to

the agents’ mechanism of action. Novel and experimental drugs with potential antiviral

properties are also being considered. Finally, therapies that modulate the

hyperinflammatory response of the host are being investigated (Table) 7-28. Antiviral

drugs are believed to be useful early in the course of the disease when it is mediated by

active viral replication. Immunomodulating agents are generally being evaluated for use

during the later pro-inflammatory process, usually manifesting as clinical deterioration in

the second week after symptom onset.

In this article, we aim to provide an objective review of the evidence behind the

proposed drug therapies for COVID-19. Electronic search in PubMed, LitCovid,

Embase, Google Scholar, and clinicaltrials.gov databases was conducted. Search terms

included SARS-CoV-2, COVID-19, 2019-nC0V, and individual drug names. Manuscripts

published in English were reviewed and relevant references were checked. The

information in this review is only as current as of the time this article is written (April 16,

2020), since new data is anticipated to emerge during this rapidly evolving pandemic.

Based on the currently available information, healthcare institutions are encouraged to

create local protocols based on available resources. A hypothetical protocol that may

serve as a starting point is depicted in Figure 2.

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Strategies Directed Against the Virus

Chloroquine and Hydroxychloroquine

Chloroquine is an aminoquinoline antimalarial drug discovered in 1934.29 In

addition to antimalarial activity, it has antiviral, anti-inflammatory, and

immunomodulatory effects. These properties have led to its use in inflammatory

rheumatologic diseases. Various mechanisms have been proposed for its antiviral

activity (Table). Chloroquine can rapidly increase the endosomal pH, thereby reducing

the fusion between SARS-CoV-2 and the endosome. By impairing terminal

glycosylation of angiotensin-converting enzyme 2 (ACE2), it decreases the affinity of

SARS-CoV-2 with ACE2, which serves as its main entry point into the cell.

Chloroquine’s antiviral activity has been tested against SARS-CoV, MERS-CoV,

human immunodeficiency virus (HIV), dengue and chikungunya.29-31 However, it failed

to show any benefit in clinical or animal models.32 Paton et al. tested chloroquine as a

prophylactic agent against influenza.33 In this randomized double-blind placebo-

controlled trial, chloroquine failed to prevent influenza infection. Similarly, after showing

a promising in vitro effect, chloroquine failed to reduce the duration of dengue viremia

and nonstructural protein 1 (NS1) antigenemia.34 Moreover, chloroquine did not improve

acute disease and was associated with more chronic arthralgia in patients with

chikungunya infection.35, 36

Assessing its activity against SARS-CoV-2, Wang et al. demonstrated, in in vitro

studies on Vero cells, that chloroquine affected the entry and post-entry stages of

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infection.7 They suggested that a daily dose of 500 mg of chloroquine would achieve the

half-maximal effective concentration (EC50) in clinical scenarios. Subsequently, Gao et

al. reported their preliminary finding on the use of chloroquine in 100 patients in Wuhan,

China, which concluded that chloroquine prevented exacerbation of pneumonia,

improved findings on lung imaging, and shortened the course of the disease.10

However, the full, peer-reviewed publication of this clinical trial is not available.

Due to a shortage of chloroquine and a superior safety profile,

hydroxychloroquine has been proposed as an alternative for the treatment of COVID-

19. Yao et al. compared the EC50 for hydroxychloroquine and chloroquine and found

that hydroxychloroquine was more potent (EC50 of 0.72 μM) than chloroquine (EC50 of

5.47 μM).8 However, in a subsequent analysis, Liu et al. found chloroquine to

demonstrate a lower EC50 across four different multiplicities of infection.37 The antiviral

effects of hydroxychloroquine were tested in a small open-label non-randomized trial by

Gautret et al.11 In this study, viral eradication was faster in hydroxychloroquine group

compared to untreated control group, and this finding was further magnified in 6 patients

who received azithromycin for prevention of bacterial infection. However, there are

major limitations of the study that raises caution in the interpretation of the results.

Indeed, the International Society of Antimicrobial Chemotherapy released a statement

that the study does not meet the Society’s expected standards.38 Only 20 of 26 patients

treated with hydroxychloroquine were included in the final analysis. The SARS-CoV-2

PCR cycle threshold (which is inversely related to the viral load) was higher in patients

treated with hydroxychloroquine and azithromycin combination (therefore, they have

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lower viral load and expected to clear sooner). The majority of the patients treated with

hydroxychloroquine had milder disease (only 22% patients had lower respiratory tract

infection). The comparator group was from a different hospital that may have different

clinical practices.39 A follow-up to this study by the same authors reported the promising

clinical and virologic outcomes of 80 patients managed with the combination of

hydroxychloroquine and azithromycin. While the authors confirmed the efficacy of this

combination therapy, this single-arm observational report lacks an all-important control

group, thereby limiting the strength of their conclusion.12 Molina et al. also investigated

the use of hydroxychloroquine and azithromycin and reported that 8 of 10 (80%)

patients remain positive for SARS-CoV-2 PCR on day 5-6 after treatment initiation.13 In

another study that is yet to be peer-reviewed, clinical improvement was observed in

25/31 (80.6%) of patients treated with hydroxychloroquine as compared to 17/31

(54.8%) in the control group that received standard treatment (including antivirals other

than hydroxychloroquine).14 Collectively, the suggestion of clinical benefit for the use of

chloroquine and hydroxychloroquine for SARS-CoV-2 should be interpreted with

caution, as it is supported only by limited, and often times conflicting, clinical data.

Accordingly, the use of chloroquine or hydroxychloroquine for COVID-19 should be

under clinical trials or treatment registries, and their off-label use outside of these trials

is not currently recommended.

Before starting hydroxychloroquine or chloroquine, patients should have

corrected QT (QTc) measured.40 Certain patient groups need to be tested for glucose-6-

phosphate dehydrogenase (G6PD) deficiency, which is associated with hemolytic

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anemia with chloroquine use. While chloroquine and hydroxychloroquine are considered

safe, the therapeutic index for chloroquine is narrow, and it has been associated with

gastrointestinal symptoms, retinopathy and deafness/tinnitus, as well as life-threatening

toxicity, including cardiomyopathy and arrhythmias and methemoglobinemia.41, 42

Several clinical trials are underway to provide real-world clinical data on the

efficacy of chloroquine and hydroxychloroquine for the treatment of COVID-19

(Supplemental Table).10 Based on the current limited data, strong recommendations

for widespread off-label clinical use cannot be made. However, the United States (US)

Food and Drug Administration (FDA) has issued an emergency use authorization of

chloroquine and hydroxychloroquine to treat hospitalized patients with COVID-19.43

Clinicians considering the use of these agents are advised to enroll their patients in

clinical trials. In the event that trial participation is not possible, careful consideration of

the risks versus potential benefits is emphasized. Detailed information on these clinical

trials is available in the Supplemental Table and on clinicaltrials.gov.28

Favipiravir

Favipiravir is a non-nucleoside RNA polymerase inhibitor that was developed for the

treatment of influenza. It has also been tested against Ebola, Marburg, Nipah, Lassa

fever and Zika viruses.44-46 Favipiravir was used alone or in combination with

monoclonal antibodies as post-exposure prophylaxis for Ebola in at least five healthcare

workers.47 Its use, in combination with ribavirin, potentiated its effect in vitro.46, 48

https://clinicaltrials.gov/

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There is very limited published in vitro and clinical data on the use of favipiravir in

coronavirus infections. In a study that was previously shared prior to peer-review but

has since been temporarily removed, favipiravir and lopinavir/ritonavir (LPV/r) were

compared in an open-label study of 80 patients during the current SARS-CoV-2

pandemic in China.15 When compared to LPV/r, favipiravir was associated with shorter

time to viral clearance (median 4 versus 11 days, p<0.001) and significant improvement

in chest imaging (improvement rate 91.43% versus 62.22%, p=0.004). Additionally, the

Japanese Health Ministry commented that the use of favipiravir in 70-80 patients did not

produce similar clinical benefit.49 These contrasting findings call for a randomized

controlled trial to assess the safety and efficacy of favipiravir for the treatment of

COVID-19 (Table).

Lopinavir/ritonavir

Lopinavir (LPV) is a protease inhibitor approved for use, in a fixed-dose

combination with ritonavir, as part of antiretroviral therapy for HIV infection. LPV/r was

used for the treatment of SARS-CoV during the 2003 outbreak. Chu et al. demonstrated

the cytopathic effect of LPV/r on SARS-CoV by in vitro antiviral susceptibility testing,

although it showed weak antiviral activity.50 In a subsequent study of 41 patients who

received LPV/r or standard of care, there was a significant difference in the incidence of

ARDS or mortality at day 21 (LPV/r = 2.4% versus control = 28.8%, p<0.001). A

multivariate analysis showed that lack of LPV/r use was independently associated with

worse outcomes. Notably, ribavirin was used concurrently with LPV/r because of its

known broad-spectrum antiviral activity and possibly an indirect immunomodulatory

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effect.51 During the 2003 SARS outbreak, Chan et al. expanded the study to 75 patients

treated with LPV/r and compared those with matched controls.52 All patients also

received steroids and ribavirin. In the initial-therapy group of 44 patients, LPV/r was

initiated within a median of 5.5 days. When compared to controls (n=634), there was

significant decrease in mortality (2.3% versus 15.6%, p<0.05), intubation rate (0%

versus 11%, p<0.05) and the proportion requiring methylprednisolone rescue (27.3%

versus 55.4%, p<0.05). However, in the rescue-therapy group of 31 patients, LPV/r was

given at a median of 18 days after symptom onset (when patients had been off

ribavirin). No statistical difference was seen between LPV/r and control group (n=343) in

mortality, intubation rate, and steroid use. These observations suggest that the efficacy

of LPV/r may be best achieved when it is given early in the course of coronavirus

infection. The MERS outbreak reignited interest in the anti-coronavirus activity of LPV/r.

In vitro data and animal model showed therapeutic potential in human MERS

infection.53-55 A clinical trial (MIRACLE) is ongoing to evaluate the efficacy of LPV/r in

combination with IFN-β.56

Because of the anecdotal clinical data from the previous coronavirus outbreaks,

LPV/r has been used for the SARS-CoV-2 outbreak in China and has been part of the

Chinese national guidelines.57 Reports of use in individual cases or series are available;

however, it is difficult to critically appraise the data because of concomitant use of

Chinese herbal and other therapies.16-19, 58 In a retrospective cohort study, Deng et al.

demonstrated that combination of arbidol with LPV/r was significantly better than LPV/r

alone for nasopharyngeal swab PCR conversion to negative after seven days (75%

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versus 35%, p<0.05), after 14 days (94% versus 52.9%, p<0.05) and improvement on

CT chest (69% versus 29%, p<0.05).22 However, in a randomized controlled open-label

study, LPV/r combination was not significantly better than the standard of care for the

management of severe COVID-19.21 This randomized controlled trial has some

noteworthy limitations. First, the mortality rate was high, which suggests the enrolment

of patients with severe COVID-19. Second, the median time from symptom onset to

randomization was 13 days, which suggests the drug may have been given too late,

when viral replication may no longer be the major factor. Notably, a total of 42% of

patients remained positive at day 28, raising the concern about its antiviral efficacy. An

absolute difference of 6.8% in 28-day mortality was observed, but this did not reach

statistical significance. Collectively, the data on the use of LPV/r for the treatment of

COVID-19 is very limited. Larger controlled clinical studies are needed to evaluate the

role of LPV/r (potentially in combination with ribavirin) in COVID-19 (Table).

Remdesivir

Remdesivir is an investigational nucleoside analog that works as an RNA-chain

terminator by inhibiting RNA-dependent viral RNA polymerase. It is a

monophosphoramidate prodrug of adenosine C-nucleoside59, and its structure is similar

to tenofovir alafenamide, which is active against HIV and hepatitis B virus.60 It was

developed by Gilead Sciences for treatment of Ebola during the 2013-2016 outbreak.

The use of remdesivir in the rhesus monkey model showed that once-daily intravenous

administration resulted in suppression of Ebola viral replication and protected animals

from lethal disease.61 Subsequently, it was used in two clinical cases (in combination

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with other therapies) with a successful outcome.62, 63 However, a randomized controlled

trial in patients with Ebola showed that remdesivir-treated patients had higher mortality

compared to three monoclonal antibodies (53.1% versus 33.5%, 35.1%, 49.7%).64

Remdesivir was demonstrated to have in vitro activity against SARS-CoV and

MERS-CoV.59, 65-67 Sheehan et al. showed that remdesivir, when combined with

interferon-beta (IFN-β) had superior antiviral properties as compared to LPV/r-IFN-β.55

Accordingly, there has been renewed interest in remdesivir for treatment of SARS-CoV-

2, especially after early anecdotal use in China suggested it may offer benefit. However,

peer-reviewed clinical data for remdesivir use in COVID-19 is still not available. In vitro

data shows that remdesivir has potent activity against SARS-CoV-2 infected Vero cells.7

Remdesivir had higher selectivity index (ratio of half-cytotoxic concentration [CC50] and

EC50) when compared to ribavirin, penciclovir, favipiravir, nafamostat and nitazoxanide

(>129.87 and >88.50 versus >3.65, >4.17, >6.46, >4.44, >16.76, respectively). Holshue

et al. reported the first successful use of remdesivir, given on a compassionate basis, in

a 35-year-old US man with COVID-19.23 Midgley et al. further reported that 3 of the first

12 cases of COVID-19 in the US received compassionate use remdesivir.24 The three

patients received remdesivir for 4-10 days, which resulted in improvement in respiratory

symptoms. All three patients had gastrointestinal symptoms and elevation of serum

transaminases. Lescure et al. reported the outcomes of the first 5 cases of COVID-19 in

Europe, including three who received remdesevir.68 One of these three, a 31-year-old

patient, discontinued remdesivir on day 5 of therapy due to elevated alanine

aminotransferase, but recovered. A second, 48-year-old patient, received 10 days of

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therapy and recovered, and a third, 80-year-old patient, received 10 days of therapy but

died on day 24.

The study of 53 patients who received compassionate remdesivir for severe

COVID-19 showed improvement in the oxygen status of 36 (68%) patients.25 The

reported mortality rate was 13%, which is lower than the anticipated mortality rate of

severe COVID-19, albeit the variability in supportive care and available resources could

also account for the difference in mortality. Moreover, the results of this cohort study are

limited by the lack of a control group, the exclusion of 8 (13%) patients from the final

analysis, and a relatively small sample size. There are several ongoing and expanding

randomized controlled trials to evaluate the safety and antiviral activity in patients with

COVID-19. Currently, the use of remdesivir is restricted to controlled clinical trials,

although it is also available through an expanded access program and a compassionate

use program for individuals who are not eligible to participate in controlled clinical trials.

Only results of these controlled clinical trials will provide the data on its true efficacy and

safety.

Based on in vitro data, it is known that remdesivir has wide therapeutic index,

high genetic barrier to resistance and long intracellular half-life.39, 60, 61 Remdesivir is

also highly selective for viral polymerases and has a low propensity for human toxicity.

Gilead has now stopped supplying remdesivir for compassionate use in adults but has

opened an expanded access program. Most of its drug supply is now reserved for

patients enrolled in several ongoing randomized controlled trials. The dose in clinical

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trials is 200mg intravenous (IV) on day 1 followed by 100 mg IV daily for a total of 5 or

10 day course (Table).

Other candidate drugs

Several compounds that are also being proposed, but with much more limited

experimental or clinical data, are nitazoxanide (an antiparasitic drug with broad-

spectrum antiviral activity), ribavirin (a broad-spectrum antiviral drug), baloxavir (an anti-

influenza drug that is undergoing clinical trials in China), among many others. Data on

these drugs are scant and very limited and will not be discussed further in this review.

Immunomodulation: Strategies Directed Against Inflammatory Cytokine Storm

A pro-inflammatory stage of COVID-19 that often presents later in the course of

infection is believed to be mediated by cytokines, including granulocyte-macrophage

colony-stimulating factor (GM-CSF) and interleukin 6 (IL-6). This is clinically manifested

by the development of severe pneumonia leading to ARDS and the requirement for

mechanical ventilation.69 This pro-inflammatory storm is associated with a high risk of

multi-organ failure and mortality. Accordingly, there has been an interest in the use of

pharmacologic compounds directed against these cytokines.

Anti-GM-CSF

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is believed to be a

key cytokine mediator of the pro-inflammatory state in patients with COVID-19. While

there has been no clinical data on its use in patients with COVID-19, mechanistically,

blocking the GM-CSF pathway is expected to reduce the severity of cytokine-induced

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inflammation. Based on this, a randomized controlled clinical trial is planned to assess

the efficacy and safety of lenzilumab, a humaneered recombinant monoclonal antibody

against GM-CSF. Lenzilumab has undergone Phase I and II studies when it was

assessed for the treatment of cytokine release syndrome associated with CAR-T

therapy. Riovant Sciences also announced that they developed an anti-GM-CSF

monoclonal antibody (Gimsilumab) to treat COVID-19 patients with ARDS. Gimsilumab

has been tested in Phase I study of healthy volunteers (results unpublished). Binding of

the monoclonal antibody to GM-CSF receptor will block the signaling pathway that leads

to cytokine release syndrome, which is also believed to characterize the pro-

inflammatory stage of COVID-19.

IL-6 inhibitors

Severe COVID-19 patients are characterized by a higher baseline IL-6 level

compared to non-severe infections.70 In critically ill patients with COVID-19, IL-6 levels

were almost tenfold higher.71 Higher IL-6 level is closely associated with SARS-CoV-2

RNAaemia.71 While it is not clear whether elevation in IL-6 has a causal association with

pro-inflammatory damage of the lungs or is just a consequence of the lung infection,

attempts at blocking IL-6 by using monoclonal antibodies directed against IL-6 receptors

have garnered interested as a potential therapeutic option.

Tocilizumab is a humanized monoclonal antibody that is used to manage

cytokine release syndrome associated with CAR-T therapy. Sarilumab is a human IgG1

monoclonal antibody approved for the treatment of rheumatoid arthritis. These IL-6

blockers bind to soluble and membrane-bound IL-6 receptors. A clinical trial involving

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sarilumab for the treatment of severe COVID-19 is ongoing, where the efficacy and

safety of sarilumab 200 mg and 400 mg dose administered intravenously over 1 hour,

are being compared with standard of care (Table). Since measurement of IL-6 levels is

not readily available in most institutions, C-reactive protein (CRP) levels may be used

as surrogate markers of the increased pro-inflammatory state. IL-6 inhibitors rapidly

decrease CRP levels after administration, and therefore, CRP levels may be used to

monitor the response to therapy.

During the current COVID-19 outbreak, a cohort of 21 febrile patients (including

17 with severe and 4 critical patients) received tocilizumab (including 3 patients who

received a second dose), and this led to defervescence, reduction in supplemental

oxygenation, and improvement in clinical symptoms. However, the absence of a control

group cautions against the optimistic interpretation of this promising data. It is unclear if

the patients would have improved otherwise with aggressive standard of care, even if

they had not received tocilizumab.26 Clinical trials are underway to evaluate the efficacy

and safety of sarilumab and tocilizumab for IL-6 inhibition in the management of COVID-

19 (Table).

It is important to reiterate that blocking IL-6 receptors may curb fever and

inflammation, but this approach also blunts the host defense against infection. IL-6

inhibition is associated with increased risk of infections, albeit this is more common after

chronic use and in combination with other immunosuppressive drugs. Ongoing clinical

trials are excluding patients with active or untreated tuberculosis and systemic bacterial

and fungal infections.

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Convalescent plasma and neutralizing antibodies

The US FDA has approved the emergency investigational use of convalescent

plasma for the treatment of critically ill patients with COVID-19.72 Convalescent plasma

is collected from COVID-19 recovered individuals who are eligible for blood donation.

The traditional screening protocol for blood donation should be satisfied. In addition, the

plasma should be collected from people with a prior confirmed diagnosis of COVID-19

who have resolved their symptoms at least 14 days prior to donation. In addition, they

should have negative PCR for SARS-CoV-2 and high SARS-CoV-2 neutralizing

antibody titers. Takeda pharmaceutical company is also developing an anti-SARS-CoV-

2 polyclonal hyperimmune globulin (TAK-888).

The use of convalescent plasma resulted in a shorter hospital stay and reduced

mortality in SARS 73 and H1N1 influenza.74 It has also been used during Ebola and

MERS outbreaks.75 A preliminary report of a series of five patients with severe COVID-

19 pneumonia complicated by ARDS showed that administration of convalescent

plasma containing neutralizing antibody (SARS-CoV-2 IgG titers greater than 1:1000 by

ELISA and neutralizing antibody titer >40) led to clinical improvement.27 There was a

normalization of body temperature in four patients within three days, the sequential

organ failure assessment score (SOFA) decreased, and viral load declined to negativity

by day 12. ARDS resolved within 12 days in four patients. These preliminary findings

are promising, but the small number and the uncontrolled nature of this study calls for

further evaluation of this treatment modality in randomized controlled clinical trials.

Several groups, including investigators from our institution and other academic

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institutions, are collaborating to achieve a common goal of developing convalescent

plasma as a viable treatment of critically ill patients with COVID-19.

Conclusion

To date, there is no proven effective drug or immunomodulator therapy for the

management of COVID-19. As this SARS-CoV-2 pandemic escalates, the search for an

effective treatment regimen is at the forefront of clinical medicine and research.

Two major approaches are being actively pursued. First, strategies directed

against the virus have led to the use of repurposed drugs (such as chloroquine,

hydroxychloroquine, LPV/r and ribavirin) and novel investigational compounds (such as

favipiravir and remdesivir). We do not yet know which, if any, of these compounds will

eventually be proven effective against SARS-COV-2. Thus, the collaboration of the

healthcare community to engage patients for participation in clinical trials is essential. In

addition to the single-center and multi-center trials, the World Health Organization

recently embarked on a large mega-trial that will compare the clinical outcome of

patients treated with chloroquine or hydroxychloroquine, LPV/r and remdesivir. Second,

there are numerous clinical trials that are aimed to determine if curbing the pro-

inflammatory state produced during COVID-19 with drugs such as IL-6 inhibitors (e.g.,

sarilumab or tocilizumab) or anti-GM-CSF compounds (e.g., lenzilumab and

gimsilumab) will lead to better clinical outcomes by preventing or reversing ARDS and

multi-organ failure.

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In addition, convalescent plasma and neutralizing antibodies are being pursued

for treatment (and maybe prevention). Vaccine development (which is outside the scope

of this review) is also given the utmost priority. The world is eagerly awaiting the

outcomes of these clinical trials, as they will inform and guide the medical community

with the best evidence to fight this pandemic. The authors strongly encourage health

care providers to use these off-label and experimental therapies under the direction of

clinical trials and treatment registries. Until the results of these properly-conducted

studies are available, there is no drug that is considered to be of proven clinical benefit

for the treatment of COVID-19.

References:

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2. Coronaviridae Study Group of the International Committee on Taxonomy of V. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol. 2020;5:536-544.

3. Shah A, Kashyap R, Tosh P, Sampathkumar P, O'Horo JC. Guide to Understanding the 2019 Novel Coronavirus. Mayo Clin Proc. 2020;95:646-652.

4. AAO-HNS: Anosmia, Hyposmia, and Dysgeusia Symptoms of Coronavirus Disease. Website. https://www.entnet.org/content/aao-hns-anosmia-hyposmia-and-dysgeusia-symptoms-coronavirus-disease. Accessed March 30, 2020.

5. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020.

6. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506.

7. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30:269-271.

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8. Yao X, Ye F, Zhang M, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020.

9. Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery. 2020;6:1-4.

10. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14:72-73.

11. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020:105949.

12. Gautret P, Lagier J-C, Parola P, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: an observational study 2020.

13. Molina JM, Delaugerre C, Goff J, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Médecine Mal. Infect. 2020.

14. Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv. 2020:2020.2003.2022.20040758.

15. Cai Q, Yang M, Liu D, et al. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering. 2020.

16. Bhatnagar T, Murhekar MV, Soneja M, et al. Lopinavir/ritonavir combination therapy amongst symptomatic coronavirus disease 2019 patients in India: Protocol for restricted public health emergency use. Indian J Med Res. 2020.

17. Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. Jama. 2020.

18. Han W, Quan B, Guo W, et al. The course of clinical diagnosis and treatment of a case infected with coronavirus disease 2019. Journal of medical virology. 2020.

19. Lim J, Jeon S, Shin HY, et al. Case of the Index Patient Who Caused Tertiary Transmission of COVID-19 Infection in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Infected Pneumonia

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20. Wang Z, Chen X, Lu Y, Chen F, Zhang W. Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment. Biosci Trends. 2020;14:64-68.

21. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020.

22. Deng L, Li C, Zeng Q, et al. Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study. J Infect. 2020.

23. Holshue ML, DeBolt C, Lindquist S, et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med. 2020;382:929-936.

24. Kujawski SA, Wong KK, Collins JP, et al. First 12 patients with coronavirus disease 2019 (COVID-19) in the United States. medRxiv. 2020:2020.2003.2009.20032896.

25. Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. New England Journal of Medicine. 2020.

26. Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with Tocilizumab. ChinaXiV. 2020;202003:v1.

27. Shen C, Wang Z, Zhao F, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020.

28. ClinicalTrials.gov. U.S. National Library of Medicine. Listed clinical studies related to the coronavirus disease (COVID-19). https://clinicaltrials.gov/ct2/results?cond=COVID-19. Accessed March 31, 2020.

29. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis. 2003;3:722-727.

30. Colson P, Rolain JM, Lagier JC, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents. 2020:105932.

31. Keyaerts E, Li S, Vijgen L, et al. Antiviral Activity of Chloroquine against Human Coronavirus OC43 Infection in Newborn Mice. Antimicrobial Agents and Chemotherapy. 2009;53:3416-3421.

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32. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res. 2020;177:104762.

33. Paton NI, Lee L, Xu Y, et al. Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial. Lancet Infect Dis. 2011;11:677-683.

34. Tricou V, Minh NN, Van TP, et al. A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults. PLoS Negl Trop Dis. 2010;4:e785.

35. Roques P, Thiberville SD, Dupuis-Maguiraga L, et al. Paradoxical Effect of Chloroquine Treatment in Enhancing Chikungunya Virus Infection. Viruses. 2018;10.

36. De Lamballerie X, Boisson V, Reynier JC, et al. On chikungunya acute infection and chloroquine treatment. Vector Borne Zoonotic Dis. 2008;8:837-839.

37. Liu J, Cao RY, Xu MY, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery. 2020;6:1-4.

38. Official Statement from International Society of Antimicrobial Chemotherapy (ISAC). https://www.isac.world/news-and-publications/official-isac-statement. Accessed April 13, 2020.

39. McCreary EK, Pogue JM, Pharmacists obotSoID. COVID-19 Treatment: A Review of Early and Emerging Options. Open Forum Infectious Diseases. 2020.

40. Giudicessi JR, Noseworthy PA, Friedman PA, Ackerman MJ. Urgent Guidance for Navigating and Circumventing the QTc-Prolonging and Torsadogenic Potential of Possible Pharmacotherapies for Coronavirus Disease 19 (COVID-19). Mayo Clin Proc. 2020.

41. Frisk-Holmberg M, Bergqvist Y, Englund U. Chloroquine intoxication. Br J Clin Pharmacol. 1983;15:502-503.

42. Fearing coronavirus, Arizona man dies after taking a form of chloroquine used to treat aquariums. https://www.cnn.com/2020/03/23/health/arizona-coronavirus-chloroquine-death/index.html. Accessed March 27, 2020.

43. Request for Emergency Use Authorization For Use of Chloroquine Phosphate or Hydroxychloroquine Sulfate Supplied From the Strategic National Stockpile for Treatment of 2019 Coronavirus Disease. https://www.fda.gov/media/136534/download. . Vol March 30, 2020Accessed March 28, 2020.

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44. Best K, Guedj J, Madelain V, et al. Zika plasma viral dynamics in nonhuman primates provides insights into early infection and antiviral strategies. Proceedings of the National Academy of Sciences of the United States of America. 2017;114:8847-8852.

45. Madelain V, Guedj J, Mentre F, et al. Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses. Antimicrobial Agents and Chemotherapy. 2017;61:e01305-01316.

46. Oestereich L, Rieger T, Ludtke A, et al. Efficacy of Favipiravir Alone and in Combination With Ribavirin in a Lethal, Immunocompetent Mouse Model of Lassa Fever. J Infect Dis. 2016;213:934-938.

47. Fischer 2nd WA, Vetter P, Bausch DG, et al. Ebola virus disease: an update on post-exposure prophylaxis. The Lancet Infectious Diseases. 2018;18:e183-e192.

48. Westover JB, Sefing EJ, Bailey KW, et al. Low-dose ribavirin potentiates the antiviral activity of favipiravir against hemorrhagic fever viruses. Antiviral research. 2016;126:62-68.

49. Japanese flu drug 'clearly effective' in treating coronavirus, says China. https://www.theguardian.com/world/2020/mar/18/japanese-flu-drug-clearly-effective-in-treating-coronavirus-says-china. Accessed March 25, 2020.

50. Chu CM, Cheng VC, Hung IF, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59:252-256.

51. Ning Q, Brown D, Parodo J, et al. Ribavirin inhibits viral-induced macrophage production of TNF, IL-1, the procoagulant fgl2 prothrombinase and preserves Th1 cytokine production but inhibits Th2 cytokine response. J Immunol. 1998;160:3487-3493.

52. Chan KS, Lai ST, Chu CM, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003;9:399-406.

53. Chan JF, Yao Y, Yeung ML, et al. Treatment With Lopinavir/Ritonavir or Interferon-beta1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. J Infect Dis. 2015;212:1904-1913.

54. de Wilde AH, Jochmans D, Posthuma CC, et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother. 2014;58:4875-4884.

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55. Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020;11:222.

56. Arabi YM, Asiri AY, Assiri AM, et al. Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-beta1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial. Trials. 2020;21:8.

57. Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment (7th edition). http://kjfy.meetingchina.org/msite/news/show/cn/3337.html. Accessed March 22, 2020.

58. Wang Z, Chen X, Lu Y, Chen F, Zhang W. Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment. Bioscience trends. 2020.

59. Gordon CJ, Tchesnokov EP, Feng JY, Porter DP, Gotte M. The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J Biol Chem. 2020;295:4773-4779.

60. Ko WC, Rolain JM, Lee NY, et al. Arguments in favour of remdesivir for treating SARS-CoV-2 infections. Int J Antimicrob Agents. 2020:105933.

61. Warren TK, Jordan R, Lo MK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531:381-385.

62. Jacobs M, Rodger A, Bell DJ, et al. Late Ebola virus relapse causing meningoencephalitis: a case report. Lancet. 2016;388:498-503.

63. Dornemann J, Burzio C, Ronsse A, et al. First Newborn Baby to Receive Experimental Therapies Survives Ebola Virus Disease. J Infect Dis. 2017;215:171-174.

64. Mulangu S, Dodd LE, Davey RT, Jr., et al. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. N Engl J Med. 2019;381:2293-2303.

65. Agostini ML, Andres EL, Sims AC, et al. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio. 2018;9.

66. de Wit E, Feldmann F, Cronin J, et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc

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67. Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017;9.

68. Lescure F-X, Bouadma L, Nguyen D, et al. Clinical and virological data of the first cases of COVID-19 in Europe: a case series. The Lancet Infectious Diseases. 2020.

69. Zhou Y, Fu B, Zheng X, et al. Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+ CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus. bioRxiv. 2020:2020.2002.2012.945576.

70. Liu T, Zhang J, Yang Y, et al. The potential role of IL-6 in monitoring severe case of coronavirus disease 2019. medRxiv. 2020:2020.2003.2001.20029769.

71. Chen X, Zhao B, Qu Y, et al. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients. medRxiv. 2020:2020.2002.2029.20029520.

72. Investigational COVID-19 Convalescent Plasma - Emergency INDs.

73. Lai ST. Treatment of severe acute respiratory syndrome. Eur J Clin Microbiol Infect Dis. 2005;24:583-591.

74. Hung IF, To KK, Lee C-K, et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clinical Infectious Diseases. 2011;52:447-456.

75. Arabi Y, Balkhy H, Hajeer AH, et al. Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol. Springerplus. 2015;4:1-8.

Figure 1. a) Chest X-ray showing diffuse bilateral opacities in a patient with COVID-19

and ARDS. b) Computed tomography scan of the chest demonstrating peripherally-

based ground glass opacities and pulmonary infiltrates.

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ARDS = acute respiratory distress syndrome; COVID-19 = Coronavirus disease 2019.

Figure 2. Hypothetical algorithm for treatment of Coronavirus disease 2019.

GM-CSF = granulocyte-macrophage colony-stimulating factor; IL-6 = interluekin-6;

LPV/r = lopinavir/ritonavir; PCR = polymerase chain reaction; SARS-CoV-2 = severe

acute respiratory syndrome coronavirus 2; US-FDA = United States Food and Drug

Administration.

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Table. Candidate therapies for the management of Coronavirus Disease-19a

Drug Proposed mechanism of

action

Evidence for SARS-CoV-2 Clinical

trials28

Hydroxychloroqu

ine and

chloroquine

Blocks viral entry by

increasing endosomal pH

and inhibiting viral fusion to

the cell membrane

Decreases affinity of ACE2

receptor for SARS-Cov-2 by

impairing terminal

glycosylation of ACE2

In vitro

Clinica

l

Wang et al.: Chloroquine affected entry and post-entry stages

of infection. 500 mg per day of chloroquine would achieve

EC50.7

Yao et al.: Hydroxychloroquine was more potent (EC50 of

0.72 μM) than chloroquine (EC50 of 5.47 μM).8

Liu et al.: Chloroquine had lower EC50 compared to

hydroxychloroquine.9

Gao et al.: Preliminary data from 100 patients demonstrated

chloroquine was better than control (peer review data not

available).10

NCT0426151

7

NCT0430866

8

NCT0432352

7

NCT0430405

3

NCT0430769

3

https://clinicaltrials.gov/ct2/show/NCT04261517




https://www.clinicaltrials.gov/ct2/show/NCT04323527






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Gautret et al.: Hydroxychloroquine was better than control at

viral eradiation. This effect was magnified by addition of

azithromycin. There are major limitations in the study

analysis.11

Gautret et al.: Confirmed the efficacy of hydroxychloroquine

and azithromycin combination but the study did not have a

control group.12

Molina et al.: 8/10 (80%) of patients had positive SARS-

CoV-2 PCR on day 5-6 after treatment with a c ombination of

hydroxychloroquine and azithromycin. The study did not

have a control group.13

Chen et al.: Hydroxychloroquine was associated with better

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clinical outcome compared to compared group (80.6% versus

54.8%, respectively). The study is pending peer-review.14

Favipiravir

RNA-dependent RNA

polymerase inhibitor

In vitro

Clinica

l

Wang et al.: EC50 of favipiravir was 61.88 which was higher

than EC50 for remdesivir and chloroquine.7

Cai et al.: The study has been temporarily removed. Open

label study comparing favipiravir and LPV/r. Favipiravir was

associated with shorter time to viral clearance (median 4 days

versus 11 days, p<0.001) and significant improvement in

chest imaging (improvement rate 91.43% versus 62.22%,

p=0.004).15

NCT0431022

8

NCT0430329

9

Lopinavir/ritonav

ir

Lopinavir is a viral protease

inhibitor that blocks viral

replication

Clinica

l

Bhatnagar et al., Young et al., Han et al., Lim et al, Wang et

al.: Case reports or case series of patients treated with LPV/r

along with other therapies including Chinese herbal

therapies.16-20

NCT0430769

3

NCT0427668

8









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Ritonavir blocks CYP3A4

thereby boosting

concentration of lopinavir

Cao et al.: Randomized open label study that showed that

LPV/r combination was not significantly better than standard

of care.21

Deng et al.: combination of arbidol with LPV/r was

significantly better than LPV/r alone for nasopharyngeal

swab test conversion.22

Remdesivir RNA-dependent RNA

polymerase inhibitor

In vitro

Clinica

l

Wang et al.: Remdesivir has potent activity against SARS-

CoV-2 infected Vero cells 7

Holshue et al.: First successful use of remdesivir in COVID-

19 patient in US.23

Midgley et al.: Compassionate use of remdesivir in three of

NCT0432376

1

NCT0430276

6

NCT0431594

8

NCT0425266








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the first 12 cases of COVID-19 in US.24

Grein et al.:Compassionate use of remdesivir in severe

COVID-19 led to improvement in oxygen status in 36/53

(68%) of patients. The study is limited by absence of control

arm.25

4

NCT0425765

6

NCT0429289

9

NCT0429273

0

IL-6 inhibitors Curbs cytokine release

syndrome by inhibiting IL-6

receptors

Clinica

l

Xu et al.: Defervescence and reduction in supplemental

oxygen requirement in 21 patients after tocilizumab use.26

NCT0431529

8

NCT0432061

5

NCT0431709

2

NCT0430670

5

NCT0432218

















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8

Anti-GM-CSF Reduce severity of cytokine

release syndrome by

inhibiting GM-CSF pathway.

No

clinical

data

availab

le as of

yet.

Convalescent

plasma

Antibody neutralization of

virus

Clinica

l

Shen et al.: Improvement in clinical status following

administration of convalescent plasma in addition to antiviral

agents in 5 patients with ARDS due to COVID-19.27

NCT0432380

0

NCT0429234

0

NCT0426485

8

aACE2 = angiotensin-converting enzyme; ARDS = acute respiratory distress syndrome; COVID-19 = coronavirus disease 2019; EC50 = half-maximal effective concentration; GM-CSF = granulocyte-macrophage colony-stimulating factor; Il-6 = interleukin 6; LPV/r = lopinavir/ritonavir; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; US = United States.








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Supplemental Table. Ongoing clinical trials registered on clinicaltrials.gov for management of COVID-19.

NCT Number Title Interventions Acronym Status Outcome Measures Phases Enrollment Study Type

Chloroquine and Hydroxychloroquine

NCT04324463 Anti-Coronavirus Therapies to Prevent Progression of Coronavirus Disease 2019 (COVID-19) Trial

Drug: Azithromycin|Drug: Chloroquine

ACT COVID19 Not yet recruiting

Outpatients: Hospital Admission or Death|Inpatients: Invasive mechanical ventilation or mortality

Phase 3 1500 Interventional

NCT04322396 Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalized Patients With COVID-19

Drug: Azithromycin|Drug: Hydroxychloroquine|Drug: Placebo oral tablet

ProPAC-COVID Not yet recruiting

Number of days alive and discharged from hospital within 14 days|Categorization of hospitalization status|Admitted to intensive care unit, if admitted to ICU then length of stay|Have used Non-invasive ventilation (NIV) during hospitalization|Mortality|Length of hospitalization|Days alive and discharged from hospital|Number of readmissions (all causes)|Number of days using non-invasive ventilation (NIV)|Change in patient's oxygen partial pressure|Change in patient's carbondioxid partial pressure|Level of pH in blood|Time for no oxygen supplement (or regular oxygen supplement "LTOT")


NCT04261517 Efficacy and Safety of Hydroxychloroquine for Treatment of Pneumonia Caused by 2019-nCoV ( HC-nCoV )

Drug: Hydroxychloroquine Completed The virological clearance rate of throat swabs, sputum, or lower respiratory tract secretions at day 3|The virological clearance rate of throat swabs, sputum, or lower respiratory tract secretions at day 5|The virological clearance rate of throat swabs, sputum, or lower respiratory tract secretions at day 7|The mortality rate of subjects at weeks 2|Number of participants with treatment-related adverse events as assessed by CTCAE v5.0|The critical illness rate of subjects at weeks 2


NCT04321278 Safety and Efficacy of Hydroxychloroquine Associated With Azithromycin in SARS-CoV2 Virus (Alliance Covid-19 Brasil II)

Drug: Hydroxychloroquine + azithromycin|Drug: Hydroxychloroquine

Not yet recruiting

Evaluation of the clinical status|All-cause mortality|Number of days free from mechanical ventilation|Duration of mechanical ventilation|Duration of hospitalization|Other secondary infections|Time from treatment start to death


NCT04322123 Safety and Efficacy of Hydroxychloroquine Associated With Azythromycin in SARS-Cov-2 Virus

Drug: Hydroxychloroquine Oral Product|Drug: Hydroxychloroquine + azithromycin

Coalition-I Not yet recruiting

Evaluation of the clinical status|Ordinal scale in 7 days|Need of intubation and mechanical ventilation|Use of mechanical ventilation during hospital stay|Use of non-invasive ventilation|Hospital Length of Stay|All-cause mortality|Thromboembolic complications|Acute renal disfunction


NCT04316377 Norwegian Coronavirus Disease 2019 Study

Drug: Hydroxychloroquine Sulfate

NO COVID-19 Not yet recruiting

Rate of decline in SARS-CoV-2 viral load|Change in National Early Warning Score score|Admission to intensive care unit|In-hospital mortality|Duration of hospital admission|Mortality at 30 and 90 days|Clinical status


NCT04315896 Hydroxychloroquine Treatment for Severe COVID-19 Pulmonary Infection (HYDRA Trial)

Drug: Hydroxychloroquine|Drug: Placebo oral tablet

HYDRA Not yet recruiting

All-cause hospital mortality|Length of hospital stay|Need of mechanical ventilation|Ventilator free days|Grade 3-4 adverse reaction


NCT04318444 Hydroxychloroquine Post Exposure Prophylaxis for Coronavirus Disease (COVID-19)


Not yet recruiting

Number of participants with symptomatic, lab-confirmed COVID-19.

Phase 2|Phase 3

1600 Interventional

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NCT04318015 Hydroxychloroquine Chemoprophylaxis in Healthcare Personnel in Contact With COVID-19 Patients (PHYDRA Trial)


PHYDRA Not yet recruiting

Symptomatic COVID-19 infection rate|Symptomatic non-COVID viral infection rate|Days of labor absenteeism|Rate of labor absenteeism|Rate of severe respiratory COVID-19 disease in healthcare personnel


NCT04321616 The Efficacy of Different Anti-viral Drugs in (Severe Acute Respiratory Syndrome-Corona Virus-2) SARS-CoV-2

Drug: Hydroxychloroquine|Drug: Remdesivir|Other: (Standard of Care) SoC

Not yet recruiting

In-hospital mortality|Occurrence and duration of mechanical ventilation|Occurrence and duration of intensive care unit (ICU) treatment|Duration of hospital admittance|28 Day mortality|Viral clearance as assessed by SARS-CoV-2 PCR in peripheral blood and nasopharyngeal airway speciemen|Occurrence of co-infections|Occurrence of organ dysfunction

Phase 2|Phase 3

700 Interventional

NCT04308668 Post-exposure Prophylaxis / Preemptive Therapy for SARS-Coronavirus-2

Drug: Hydroxychloroquine|Other: Placebo

COVID-19 PEP Recruiting Incidence of COVID19 Disease among those who are asymptomatic at trial entry|Ordinal Scale of COVID19 Disease Severity at 14 days among those who are symptomatic at trial entry|Incidence of Hospitalization|Incidence of Death|Incidence of Confirmed SARS-CoV-2 Detection|Incidence of Symptoms Compatible with COVID19 (possible disease)|Incidence of All-Cause Study Medicine Discontinuation or Withdrawal|Overall symptom severity at 5 and 14 day


NCT04323631 Hydroxychloroquine for the Treatment of Patients With Mild to Moderate COVID-19 to Prevent Progression to Severe Infection or Death

Drug: Hydroxychloroquine|Other: The control group will not receive hydroxychloroquine

Not yet recruiting

Number patients developing severe infection or death Early Phase 1

1116 Interventional

NCT04323527 Chloroquine Diphosphate for the Treatment of Severe Acute Respiratory Syndrome Secondary to SARS-CoV2

Drug: Chloroquine diphosphate CloroCOVID19 Recruiting Absolute mortality at day 28|Absolute mortality on days 7 and 14|Improvement in overall subject's clinical status assessed in standardized clinical questionnaires on days 14 and 28|Improvement in daily clinical status assessed in standardized clinical questionnaires during hospitalization|Duration of supplemental oxygen (if applicable)|Duration of mechanical ventilation (if applicable)|Absolute duration of hospital stay in days|Prevalence of grade 3 and 4 adverse events|Prevalence of serious adverse events|Change in serum creatinine level|Change in serum troponin I level|Change in serum aspartate aminotransferase level|Change in serum CK-MB level|Change in detectable viral load in respiratory tract swabs|Viral concentration in blood samples|Absolute number of causes leading to participant death (if applicable)


NCT04303507 Chloroquine/ Hydroxychloroquine Prevention of Coronavirus Disease (COVID-19) in the Healthcare Setting

Drug: Chloroquine or Hydroxychloroquine|Drug: Placebo

COPCOV Not yet recruiting

Number of symptomatic COVID-19 infections|Symptoms severity of COVID-19|Number of asymptomatic cases of COVID-19|Number of symptomatic acute respiratory illnesses|Severity of symptomatic acute respiratory illnesses

Not Applicable

40000 Interventional

NCT04303299 Various Combination of Protease Inhibitors, Oseltamivir, Favipiravir, and Hydroxychloroquine for Treatment of COVID19 : A Randomized Control Trial

Drug: Oral THDMS-COVID19

Not yet recruiting

SARS-CoV-2 eradication time|Number of patient with Death|Number of patient with Recovery adjusted by initial severity in each arm|Number of day With ventilator dependent adjusted by initial severity in each arm|Number of patient developed Acute Respiratory Distress Syndrome After treatment


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NCT04304053 Treatment of COVID-19 Cases and Chemoprophylaxis of Contacts as Prevention

Drug: Antiviral treatment and prophylaxis|Other: Standard Public Health measures

HCQ4COV19 Recruiting Effectiveness of chemoprophylaxis assessed by incidence of secondary COVID-19 cases|The virological clearance rate of throat swabs, sputum, or lower respiratory tract secretions at days 3|The mortality rate of subjects at weeks 2|Proportion of participants that drop out of study|Proportion of participants that show non-compliance with study drug


Favipiravir

NCT04310228 Favipiravir Combined With Tocilizumab in the Treatment of Corona Virus Disease 2019

Drug: Favipiravir Combined With Tocilizumab|Drug: Favipiravir|Drug: Tocilizumab

Recruiting Clinical cure rate|Viral nucleic acid test negative conversion rate and days from positive to negative|Duration of fever|Lung imaging improvement time|Mortality rate because of Corona Virus Disease 2019|Rate of non-invasive or invasive mechanical ventilation when respiratory failure occurs|Mean in-hospital time

Not Applicable

150 Interventional



Not yet recruiting



Lopinavir/ritonavir

NCT04295551 Multicenter Clinical Study on the Efficacy and Safety of Xiyanping Injection in the Treatment of New Coronavirus Infection Pneumonia (General and Severe)

Drug: Lopinavir / ritonavir tablets combined with Xiyanping injection|Drug: Lopinavir/ritonavir treatment

Not yet recruiting

Clinical recovery time Not Applicable

80 Interventional

NCT04321174 COVID-19 Ring-based Prevention Trial With Lopinavir/Ritonavir

Drug: Lopinavir/ritonavir CORIPREV-LR Not yet recruiting

Microbiologic evidence of infection|Adverse events|Symptomatic COVID-19 disease|Seropositivity|Days of hospitalization attributable to COVID-19 disease|Respiratory failure requiring ventilatory support attributable to COVID-19 disease|Mortality|Short-term psychological impact of exposure to COVID-19 disease|Long-term psychological impact of exposure to COVID-19 disease|Health-related quality of life


NCT04307693 Comparison of Lopinavir/Ritonavir or Hydroxychloroquine in Patients With Mild Coronavirus Disease (COVID-19)

Drug: Lopinavir/ritonavir|Drug: Hydroxychloroquine sulfate

Recruiting Viral load|Viral load change|Time to clinical improvement (TTCI)|Percentage of progression to supplemental oxygen requirement by day 7|Time to NEWS2 (National Early Warning Score 2) of 3 or more maintained for 24 hours by day 7|Time to clinical failure, defined as the time to death, mechanical ventilation, or ICU admission|Rate of switch to Lopinavir/ritonavir or hydroxychloroquine by day 7|adverse effects|Concentration of Lopinavir/ritonavir and hydroxychloroquine


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NCT04321993 Treatment of Moderate to Severe Coronavirus Disease (COVID-19) in Hospitalized Patients

Drug: Lopinavir/ritonavir|Drug: Hydroxychloroquine sulfate|Drug: Baricitinib (janus kinase inhibitor)|Drug: Sarilumab (anti-IL-6 receptor)

Not yet recruiting

Clinical status of subject at day 15 (on a 7 point ordinal scale).|Status on an ordinal scale assessed daily while hospitalized and on days 15 and 29 and 180.|Length of time to clinical improvement|Number of participants with normal pulmonary function and normal O2 saturation on days 11, 15 and 29|Number of participants that developed Acute Respiratory Distress Syndrome (ARDS) after treatment|Length of time to clinical progression|Cause of death (if applicable)|Sequential Organ Failure Assessment (SOFA) score, daily while hospitalized and on days 15 and 29. (Initial, highest, deltas and mean)|Length of time to normalization of fever|Length of time to normalization of oxygen saturation|Duration of supplemental oxygen (if applicable)|Duration of mechanical ventilation (if applicable)|Duration of hospitalization|Adverse events


NCT04276688 Lopinavir/ Ritonavir, Ribavirin and IFN-beta Combination for nCoV Treatment

Drug: Lopinavir/ritonavir|Drug: Ribavirin|Drug: Interferon Beta-1B

Recruiting Time to negative NPS|Time to negative saliva|Time to clinical improvement|Hospitalisation|Mortality|Immune reaction|Adverse events|Time to negative all clinical specimens




Not yet recruiting



Remdesivir

NCT04323761 Expanded Access Treatment Protocol: Remdesivir (RDV; GS-5734) for the Treatment of SARS-CoV2 (CoV) Infection

Drug: Remdesivir Available Expanded Access:Treatment IND/Protocol

NCT04302766 Expanded Access Remdesivir (RDV; GS-5734â„¢)

Drug: Remdesivir Available Expanded Access:Intermediate-size Population|Treatment IND/Protocol

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NCT04315948 Trial of Treatments for COVID-19 in Hospitalized Adults

Drug: Remdesivir|Drug: Lopinavir/ritonavir|Drug: Interferon Beta-1A|Drug: Hydroxychloroquine|Other: Standard of care

DisCoVeRy Recruiting Percentage of subjects reporting each severity rating on a 7-point ordinal scale|Percentage of subjects reporting each severity rating on a 7-point on an ordinal scale|The time to discharge or to a NEWS of â‰¤ 2 and maintained for 24 hours, whichever occurs first.|Number of oxygenation free days in the first 28 days|Incidence of new oxygen use, non-invasive ventilation or high flow oxygen devices during the trial.|Duration of new oxygen use, non-invasive ventilation or high flow oxygen devices during the trial.|Ventilator free days in the first 28 days|Incidence of new mechanical ventilation use during the trial.|Hospitalization|Mortality|Cumulative incidence of serious adverse events (SAEs)|Cumulative incidence of Grade 3 and 4 adverse events (AEs)|Number of participants with a discontinuation or temporary suspension of study drugs (for any reason)|Changes from baseline in blood white cell count|Changes from baseline in haemoglobin|Changes from baseline in platelets|Changes from baseline in creatinine|Changes from baseline in blood electrolytes (including kaliemia)|Changes from baseline in prothrombine time|Changes from baseline in international normalized ratio (INR)|Changes from baseline in glucose|Changes from baseline in total bilirubin|Changes from baseline in alanine aminotransferase (ALT)|Changes from baseline in aspartate aminotransferase (AST)


NCT04252664 Mild/Moderate 2019-nCoV Remdesivir RCT

Drug: Remdesivir|Drug: Remdesivir placebo

Recruiting Time to Clinical recoveryTime to Clinical Recovery (TTCR)|All cause mortality|Frequency of respiratory progression|Time to defervescence (in those with fever at enrolment)|Time to cough reported as mild or absent (in those with cough at enrolment rated severe or moderate)|Time to dyspnea reported as mild or absent (on a scale of severe, moderate, mild absent, in those with dyspnoea at enrolment rated as severe or moderate,)|Frequency of requirement for supplemental oxygen or non-invasive ventilation|Time to 2019-nCoV RT-PCR negative in upper respiratory tract specimen|Change (reduction) in 2019-nCoV viral load in upper respiratory tract specimen as assessed by area under viral load curve.|Frequency of requirement for mechanical ventilation|Frequency of serious adverse events


NCT04257656 Severe 2019-nCoV Remdesivir RCT

Drug: Remdesivir|Drug: Remdesivir placebo

Recruiting Time to Clinical Improvement (TTCI) [Censored at Day 28]|Clinical status|Time to Hospital Discharge OR NEWS2 (National Early Warning Score 2) of â‰¤ 2 maintained for 24 hours.|All cause mortality|Duration (days) of mechanical ventilation|Duration (days) of extracorporeal membrane oxygenation|Duration (days) of supplemental oxygenation|Length of hospital stay (days)|Time to 2019-nCoV RT-PCR negativity in upper and lower respiratory tract specimens|Change (reduction) in 2019-nCoV viral load in upper and lower respiratory tract specimens as assessed by area under viral load curve.|Frequency of serious adverse drug events


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NCT04292899 Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734â„¢) in Participants With Severe Coronavirus Disease (COVID-19)

Drug: Remdesivir|Drug: Standard of Care

Recruiting Proportion of Participants With Normalization of Fever and Oxygen Saturation Through Day 14|Proportion of Participants With Treatment Emergent Adverse Events Leading to Study Drug Discontinuation


NCT04292730 Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734â„¢) in Participants With Moderate Coronavirus Disease (COVID-19) Compared to Standard of Care Treatment

Drug: Remdesivir|Drug: Standard of Care

Recruiting Proportion of Participants Discharged by Day 14|Proportion of Participants With Treatment Emergent Adverse Events Leading to Study Drug Discontinuation


NCT04280705 Adaptive COVID-19 Treatment Trial (ACTT)

Other: Placebo|Drug: Remdesivir

Recruiting Percentage of subjects reporting each severity rating on an 8-point ordinal scale|Change from baseline in alanine transaminase (ALT)|Change from baseline in aspartate transaminase (AST)|Change from baseline in creatinine|Change from baseline in glucose|Change from baseline in hemoglobin|Change from baseline in platelets|Change from baseline in prothrombin time (PT)|Change from baseline in total bilirubin|Change from baseline in white blood cell count with differential|Change in National Early Warning Score (NEWS) from baseline|Clinical status using ordinal scale|Cumulative incidence of Grade 3 and 4 adverse events (AEs)|Cumulative incidence of serious adverse events (SAEs)|Discontinuation or temporary suspension of infusions|Duration of hospitalization|Duration of new non-invasive ventilation or high flow oxygen use|Duration of new oxygen use|Duration of new ventilator or extracorporeal membrane oxygenation (ECMO) use|Incidence of new non-invasive ventilation or high flow oxygen use|Incidence of new oxygen use|Incidence of new ventilator or extracorporeal membrane oxygenation (ECMO) use|Mean change in the ordinal scale|Number of non-invasive ventilation/high flow oxygen free days|Number of oxygenation free days|Subject 14-day mortality|Subject 28-day mortality|Time to an improvement of one category using an ordinal scale|Time to an improvement of two categories using an ordinal scale|Time to discharge or to a National Early Warning Score (NEWS) of </= 2 and maintained for 24 hours, whichever occurs first|Ventilator/extracorporeal membrane oxygenation (ECMO) free days


Antiinfluenza

NCT04261270 A Randomized,Open,Controlled Clinical Study to Evaluate the Efficacy of ASC09F and Ritonavir for 2019-nCoV Pneumonia

Drug: ASC09F+Oseltamivir|Drug: Ritonavir+Oseltamivir|Drug: Oseltamivir

Recruiting Rate of comprehensive adverse outcome|Time of clinical remission|Rate of no fever|Rate of no cough|Rate of no dyspnea|Rate of no need for oxygen inhalation|Rate of undetectable viral RNA|Rate of mechanical ventilation|Rate of ICU admission|Rate and time of CRP,ES,Biochemical criterion(CK,ALT,Mb)recovery


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Not yet recruiting



IL-6

NCT04322773 Anti-il6 Treatment of Serious COVID-19 Disease With Threatening Respiratory Failure

Drug: RoActemra iv|Drug: RoActemra sc|Drug: Kevzara sc|Other: Standard medical care

TOCIVID Not yet recruiting

Time to independence from supplementary oxygen therapy|Number of deaths|Days out of hospital and alive|Ventilator free days alive and out of hospital|C-reactive protein (CRP) level|Number of participants with treatment-related side effects as assessed by Common Terminology Criteria for Adverse Event (CTCAE)


NCT04324073 Cohort Multiple Randomized Controlled Trials Open-label of Immune Modulatory Drugs and Other Treatments in COVID-19 Patients - Sarilumab Trial - CORIMUNO-19 - SARI

Drug: Sarilumab CORIMUNO-SARI

Not yet recruiting

Survival without needs of ventilator utilization at day 14.|WHO progression scale <=5 at day 4|Cumulative incidence of successful tracheal extubation (defined as duration extubation > 48h) at day 14|WHO progression scale <=7 at day 4|WHO progression scale|Survival|28-day ventilator free-days|respiratory acidosis at day 4|PaO2/FiO2 ratio|time to oxygen supply independency|duration of hospitalization|time to negative viral excretion|time to ICU discharge|time to hospital discharge

Phase 2|Phase 3

180 Interventional

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NCT04315298 Evaluation of the Efficacy and Safety of Sarilumab in Hospitalized Patients With COVID-19

Drug: Sarilumab|Drug: Placebo Recruiting Time to resolution of fever for at least 48 hours without antipyretics for 48 hours|Percentage of patients reporting each severity rating on a 6-point ordinal scale|Time to improvement in oxygenation for at least 48 hours|Mean change in the 6-point ordinal scale|Clinical status using the 6-point ordinal scale|Time to improvement in one category from admission using the 6-point ordinal scale|Time to resolution of fever for at least 48 hours without antipyretics by clinical severity|Time to resolution of fever for at least 48 hours without antipyretics by baseline IL-6 levels|Time to improvement in oxygenation for at least 48 hours by clinical severity|Time to improvement in oxygenation for at least 48 hours by baseline IL-6 levels|Time to resolution of fever and improvement in oxygenation for at least 48 hours|Time to change in National Early Warning Score 2 (NEWS2) scoring system|Time to score of <2 maintained for 24 hours in NEWS2 scoring system|Mean change in NEWS2 scoring system|Number of days with fever|Number of patients alive off oxygen|Number of days of resting respiratory rate >24 breaths/min|Number of days with hypoxemia|Number of days of supplemental oxygen use|Time to saturation â‰¥94% on room air|Number of ventilator free days in the first 28 days|Number of patients requiring initiation of mechanical ventilation|Number of patients requiring non-invasive ventilation|Number of patients requiring the use of high flow nasal cannula|Number of patients admitted into an intensive care unit (ICU)|Number of days of hospitalization among survivors|Number of deaths due to any cause|Incidence of serious adverse events|Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection|Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection in patients with grade 4 neutropenia|Incidence of hypersensitivity reactions|Incidence of infusion reactions|Incidence of gastrointestinal perforation|White blood cell count|Hemoglobin levels|Platelet count|Creatinine levels|Total bilirubin level|Alanine aminotransferase level|Aspartate aminotransferase level

Phase 2|Phase 3

400 Interventional

NCT04315480 Tocilizumab for SARS-CoV2 Severe Pneumonitis

Drug: Tocilizumab Not yet recruiting

arrest in deterioration of pulmonary function|improving in pulmonary function|need of oro-tracheal intubation|death


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NCT04320615 A Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients With Severe COVID-19 Pneumonia

Drug: Tocilizumab (TCZ)|Drug: Placebo

COVACTA Not yet recruiting

Clinical Status Assessed Using a 7-Category Ordinal Scale|Time to Clinical Improvement (TTCI), Defined as a National Early Warning Score 2 (NEWS2) of </= 2 Maintained for 24 Hours|Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status|Incidence of Mechanical Ventilation|Ventilator-Free Days to Day 28|Organ Failure-Free Days to Day 28|Incidence of Intensive Care Unit (ICU) Stay|Duration of ICU Stay|Time to Clinical Failure|Mortality Rate|Time to Hospital Discharge|Duration of Time on Supplemental Oxygen|Percentage of Participants with Adverse Events|COVID-19 (SARS-CoV-2) Viral Load Over Time|Time to Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR) Virus Negativity|Proportion of Participants with Post-Treatment Infection|Serum Concentration of IL-6|Serum Concentration of sIL-6R|Serum Concentration of Ferritin|Serum Concentration of C-Reactive Protein (CRP)|Serum Concentration of TCZ


NCT04317092 Tocilizumab in COVID-19 Pneumonia (TOCIVID-19)

Drug: Tocilizumab Injection TOCIVID-19 Recruiting One-month mortality rate|Interleukin-6 level|Lymphocyte count|CRP (C-reactive protein) level|PaO2 (partial pressure of oxygen) / FiO2 (fraction of inspired oxygen, FiO2) ratio (or P/F ratio)|Change of the SOFA (Sequential Organ Failure Assessment)|Number of participants with treatment-related side effects as assessed by Common Terminology Criteria for Adverse Event (CTCAE) version 5.0|Radiological response|Duration of hospitalization|Remission of respiratory symptoms


NCT04306705 Tocilizumab vs CRRT in Management of Cytokine Release Syndrome (CRS) in COVID-19

Drug: Tocilizumab|Other: Standard of care|Procedure: Continuous renal replacement therapy

TACOS Recruiting Proportion of Participants With Normalization of Fever and Oxygen Saturation Through Day 14|Duration of hospitalization|Proportion of Participants With Normalization of Fever Through Day 14|Change from baseline in white blood cell and differential count|Time to first negative in 2019 novel Corona virus RT-PCR test|All-cause mortality|Change from baseline in hsCRP|Change from baseline in cytokines IL-1Î², IL-10, sIL-2R, IL-6, IL-8 and TNF-Î±|Change from baseline in proportion of CD4+CD3/CD8+CD3 T cells

120 Observational

NCT04322188 An Observational Case-control Study of the Use of Siltuximab in ARDS Patients Diagnosed With COVID-19 Infection

SISCO Recruiting Cohort A: reduction of the need of invasive ventilation or 30-day mortality|Cohort B: reduction of mortality|Cohort A Reduction of the need of time of ventilatory support|Cohort B Percentage of patients that undergo to tracheostomy|Cohort B Improvement of the lung function assessed by radiologic findings

50 Observational

Convalescent plasma

NCT04323800 Efficacy and Safety Human Coronavirus Immune Plasma (HCIP) vs. Control (SARS-CoV-2 Non-immune Plasma) Among Adults Exposed to COVID-19

Biological: Anti- SARS-CoV-2 Plasma|Biological: SARS-CoV-2 non-immune Plasma

CSSC-001 Not yet recruiting

Cumulative incidence of composite outcome of disease severity|Anti-SARS-CoV-2 titers|Rates of SARS-CoV-2 PCR positivity|Duration of SARS-CoV-2 PCR positivity|Peak quantity levels of SARS-CoV-2 RNA


NCT04325672 Convalescent Plasma to Limit Coronavirus Associated Complications

Biological: Convalescent Plasma

Not yet recruiting

RNA in SARS-CoV-2|ICU Admissions|Hospital Mortality|Hospital Length of Stay (LOS)|Type of respiratory support|Duration of respiratory support


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NCT04321421 Hyperimmune Plasma for Critical Patients With COVID-19

Other: hyperimmune plasma COV19-PLASMA

Active, not recruiting

death|time to extubation|length of intensive care unit stay|time to CPAP weaning|viral load|immune response

Not Applicable

49 Interventional

NCT04292340 Anti-SARS-CoV-2 Inactivated Convalescent Plasma in the Treatment of COVID-19

Recruiting The virological clearance rate of throat swabs, sputum, or lower respiratory tract secretions at day 1|The virological clearance rate of throat swabs, sputum, or lower respiratory tract secretions at day 3|The virological clearance rate of throat swabs, sputum, or lower respiratory tract secretions at day 7|Numbers of participants with different Clinical outcomes|Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

15 Observational

NCT04264858 Treatment of Acute Severe 2019-nCoV Pneumonia With Immunoglobulin From Cured Patients

Drug: Immunoglobulin of cured patients|Drug: Î³-Globulin

Not yet recruiting

Time to Clinical Improvement (TTCI)|Clinical status assessed by the ordinal scale|The differences in oxygen intake methods|Duration (days) of supplemental oxygenation|Duration (days) of mechanical ventilation|The mean PaO2/FiO2|The lesions of the pulmonary segment numbers involved in pulmonary CT [ every 7 days]|Time to 2019-nCoV RT-PCR negativity in respiratory tract specimens [every 3 days]|Dynamic changes of 2019-nCoV antibody titer in blood|Length of hospital stay (days)|All cause mortality

Not Applicable

10 Interventional

Reference: ClinicalTrials.gov. U.S. National Library of Medicine. Listed clinical studies related to the coronavirus disease (COVID-19). https://clinicaltrials.gov/ct2/results?cond=COVID-19. Accessed March 31, 2020.

https://clinicaltrials.gov/ct2/results?cond=COVID-19

preproo - mosby · in december 2019, a novel coronavirus outbreak was reported from wuhan in the...

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