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Contents lists available at ScienceDirect

Drug Resistance Updates

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

FDA approved drugs with pharmacotherapeutic potential for SARS-CoV-2 (COVID-19) therapy Sylwester Drożdżala, Jakub Rosikb, Kacper Lechowiczc, Filip Machajb, Katarzyna Kotfisc, Saeid Ghavamid, Marek J. Łose,* a Department of Pharmacokinetics and Monitored Therapy, Pomeranian Medical University in Szczecin, Poland bDepartment of Pathology, Pomeranian Medical University in Szczecin, Poland c Department of Anaesthesiology, Intensive Therapy and Acute Intoxications, Pomeranian Medical University in Szczecin, Poland dDepartment of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada e Biotechnology Centre, Silesian University of Technology, Krzywoustego 8 Str., 44-100, Gliwice, Poland

A R T I C L E I N F O

Keywords: Coronavirus SARS-CoV-2 Chloroquine Lopinavir Remdesivir Ribavirin Ritonavir

A B S T R A C T

In December 2019, a novel SARS-CoV-2 coronavirus emerged, causing an outbreak of life-threatening pneu- monia in the Hubei province, China, and has now spread worldwide, causing a pandemic. The urgent need to control the disease, combined with the lack of specific and effective treatment modalities, call for the use of FDA- approved agents that have shown efficacy against similar pathogens. Chloroquine, remdesivir, lopinavir/rito- navir or ribavirin have all been successful in inhibiting SARS-CoV-2 in vitro. The initial results of a number of clinical trials involving various protocols of administration of chloroquine or hydroxychloroquine mostly point towards their beneficial effect. However, they may not be effective in cases with persistently high viremia, while results on ivermectin (another antiparasitic agent) are not yet available. Interestingly, azithromycin, a macrolide antibiotic in combination with hydroxychloroquine, might yield clinical benefit as an adjunctive. The results of clinical trials point to the potential clinical efficacy of antivirals, especially remdesivir (GS-5734), lopinavir/ ritonavir, and favipiravir. Other therapeutic options that are being explored involve meplazumab, tocilizumab, and interferon type 1. We discuss a number of other drugs that are currently in clinical trials, whose results are not yet available, and in various instances we enrich such efficacy analysis by invoking historic data on the treatment of SARS, MERS, influenza, or in vitro studies. Meanwhile, scientists worldwide are seeking to discover novel drugs that take advantage of the molecular structure of the virus, its intracellular life cycle that probably elucidates unfolded-protein response, as well as its mechanism of surface binding and cell invasion, like an- giotensin converting enzymes-, HR1, and metalloproteinase inhibitors.

Introduction

Coronaviruses (CoVs) are single-stranded RNA viruses that belong to the Coronaviridae family. They spread among a wide range of hosts, presenting clinically with an array of symptoms, ranging from common cold-like to severe, sometimes lethal, respiratory infection. The new virus, responsible for the pandemic, was initially termed as “2019- nCoV”, but it has since been renamed “SARS-CoV-2” by the Coronavirus Study Group (CSG), a body that belongs to the International Committee on Taxonomy of Viruses (ICTV), as it is believed to be familiar with the SARS-CoV, a pathogen that causes severe acute respiratory syndrome (SARS). The recent SARS-CoV-2 is closely associated with SARS-CoV, sharing 80 % identity in RNA sequence (Gorbalenya et al., 2020; Chan

et al., 2020). With first cases in humans being recorded in December 2019, SARS-CoV-2 is responsible for an outbreak of respiratory disease called COVID-19 (Coronavirus Disease 2019). The full spectrum of COVID-19 ranges from benign, self-resolving respiratory distress to severe progressive pneumonia, multiple organ failure, and death (Huang et al., 2020a). The city of Wuhan, in the province of Hubei in central China has been declared as the epicenter of the pandemic, with Huanan seafood market being one of the first locations where SARS- CoV-2 potentially crossed the species barrier at the animal-human in- terface. Pioneering research undertaken in Shenzhen, near Hong Kong, by a group of clinicians and scientists from the University of Hong Kong, provided the first piece of evidence, that SARS-CoV-2 can been transmitted from human-to-human (Chan et al., 2020). The new threat

https://doi.org/10.1016/j.drup.2020.100719 Received 4 April 2020; Received in revised form 10 July 2020; Accepted 13 July 2020

⁎ Corresponding author. E-mail address: [email protected] (M.J. Łos).

Drug Resistance Updates 53 (2020) 100719

Available online 15 July 2020 1368-7646/ Crown Copyright © 2020 Published by Elsevier Ltd. All rights reserved.

T

quickly spread from China and is currently classified as a pandemic by the World Health Organization (WHO). Many countries are im- plementing extraordinary measures in order to provide their societies with adequate strategies of disease prevention and monitoring (Chan et al., 2020; Zhou et al., 2020).

For the time being, there is neither a vaccination or a specific SARS- CoV-2 targeted antiviral treatment available. Multiple countries have attempted varying pharmacologic strategies to combat the disease, in- volving currently established antivirals, different modes of oxygen therapy or mechanical ventilation. COVID-19 pandemic requires rapid development of efficacious therapeutic strategies, in the pursuit of which three concepts are being applied: (i) The first approach relies on testing currently known antiviral agents and verifying their clinical usefulness (Kim et al., 2016; Lu, 2020). (ii) Another modality is based on molecular libraries and databases, allowing for high computing power and simultaneous verification of millions of potential agents (Lu, 2020; Channappanavar et al., 2017). (iii) Lastly, the third strategy in- volves targeted therapy, intended to disrupt the genome and func- tioning of the virus. Precisely designed particles would disrupt the crucial steps of viral infection, such as cell surface binding and inter- nalization. Unfortunately, in vitro activity does not necessarily translate into efficacy in the in vivo setting, due to differing pharmacodynamic and pharmacokinetic properties (Lu, 2020; Zumla et al., 2016). The main groups of therapeutic agents that can be useful in COVID-19 treatment involve antiviral drugs, selected antibiotics, antimalarials, and immunotherapeutic drugs. In the present paper, we aim to sum- marize current progress and insights that have emerged from the use of pharmaceuticals in COVID-19.

Hydroxychloroquine and other antimalarials

In one of the newest dissertations published by a French team of doctors, a positive influence of hydroxychloroquine (HCQ) in patients infected by SARS-CoV-2 was observed (Gautret et al., 2020). Further- more, another in vitro trial showed that both chloroquine (CQ) and its hydroxylated derivative, HCQ, possess beneficial properties. HCQ, an agent with universally established antimalarial, anti-inflammatory, and analgesic properties, is widely used in the treatment of malaria. The US Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC) are currently working on establishing rando- mized clinical trials that aim to confirm the usefulness of CQ and its derivatives in combating CoV-2 virus infection (Anon, 2020a, b). In the beginning of February 2020, China included CQ with its derivatives as one of the therapeutic options in SARS-CoV-2 treatment, with South Korea soon following this path (Gao et al., 2020; Sung-sun, 2020). The mechanism of action of antimalarial agents has not been well eluci- dated – it is believed to be pleiotropic, affecting T-cells, cytokine pro- duction, and others. Graphical representation of HCQ action can be seen in Fig. 1. Additional anti-inflammatory effect can be attributed to the inhibition of extracellular matrix metalloproteinases (Nowell and Quaranta, 1985; Lafyatis et al., 2006; Wozniacka et al., 2006). In this case, the potential mechanism of action of CQ and its hydroxylated derivative is attributed to the blockade of viral infection via an alkali- zation of endosomal (and lysosomal) pH; it should be emphasized that the above acidic pH is required for virus-host cell fusion (Adar et al., 2012; Zhitomirsky and Assaraf, 2016, 2015). Furthermore, the agents are believed to disrupt SARS-CoV cell receptor glycosylation (Wang et al., 2020a).

It has been shown that HCQ presents in vitro antiviral properties against SARS-CoV (Biot et al., 2006). Its clinical safety profile is su- perior to that of CQ (in a long-term setting), which allows for higher daily dose, and results in fewer drug-drug interactions (Yao et al., 2020; Marmor et al., 2016). A clinical trial aiming to assess the influence of HCQ on the outcome of patients infected with SARS-CoV-2 by Gautret et al., compared patients receiving HCQ and controls, concentrating on viral load reduction (Gautret et al., 2020) (all clinical trials are

summarized in Table 1 and Fig. 2). The study enrolled hospitalized patients with confirmed COVID-19. Patients were stratified into three categories: asymptomatic (16.7 %); upper respiratory tract infection (URTI; 61.1 %), presenting as rhinitis, pharyngitis, or isolated fever and muscle pain; lower respiratory tract infections (LRTI; 22.2 %), who suffered from symptoms of pneumonia or bronchitis. Twenty patients were administered HCQ sulfate orally, and 16 served as the control group. Among patients treated with HCQ, 6 were also treated with azithromycin, in order to prevent superimposed bacterial infection. The percentage of patients with absence of viral loads on nasopharyngeal swab sample RT-PCR was significantly higher in the treatment group than in controls, on days 3, 4, 5 and 6 of follow-up. On day 6, which was considered the endpoint, in 70 % of patients treated with HCQ viral load disappearance was observed, in comparison with 12.5 % in the control group (p=0.001) (Gautret et al., 2020).

Another study compiling the results of over 100 patients showed that the addition of CQ phosphate is superior to standard supportive care and hence contributing to prevention of the deterioration of pneumonia. Investigators observed improved lung imaging findings, improved negative conversion, and shortening of the disease course. No severe adverse events were noted in the study. CQ phosphate was re- commended to be introduced into the next edition of National Health Commission of the People’s Republic of China guidelines on prevention, diagnosis, and treatment of pneumonia caused by COVID-19 (Gao et al., 2020).

In February 2020, a randomized clinical trial on 62 patients was established in Renmin Hospital of Wuhan University to determine the efficacy of HCQ in patients with COVID-19. The trial involved 5-day HCQ treatment (400mg/day), during which patients were examined 3 times a day, including temperature measurement and assessment of cough. CT was performed at baseline and once again after 5 days. In the HCQ arm, significantly shorter body temperature normalization and cough remission times were noted. In addition, radiological improve- ment in pneumonia was observed more frequently in patients from the HCQ group (80.6 % vs 54.8 %). Despite the rather limited sample size, the trial demonstrated that the use of HCQ can improve patient prog- nosis, accelerate remission, and improve clinical status (Chen et al., 2020a).

Teng et al., showed that administration of HCQ in patients with persistent mild to moderate COVID-19 did not improve the probability of negative conversion, in comparison with standard of care alone. One hundred and fifty patients were included in this study, with 75 assigned to HCQ plus standard of care, whereas the remaining 75 patients were treated with standard of care only. Results of HCQ group did not differ significantly from the results of the standard of care group (Tang et al., 2020).

In a recent study, HCQ administration resulted in earlier recovery, without affecting overall mortality. The study was conducted on a group of 522 patients, 127 of which were symptomatic, while the re- maining 395 patients had no clinical manifestations at baseline. Their COVID-19 status was confirmed by RT-PCR. Asymptomatic patients treated with HCQ recovered earlier (average recovery time= 5.4 days) compared to asymptomatic patients who did not receive any treatment (average recovery time=7.6 days) (Bhandari et al., 2020).

In conclusion: CQ is a cheap and relatively safe drug that has been in clinical use for over 70 years (Ciak and Hahn, 1966; Chu et al., 2018), therefore can be a potential candidate for SARS-CoV-2 treatment (Cortegiani et al., 2020). Despite promising results, it is essential to consider all safety measures and treat with this medication only as a supplementary form of treatment. Moreover, the initial enthusiasm surrounding HCQ and CQ was curbed after both were discontinued from SOLIDARITY trial due to the lack of benefit (WHO, 2020). This, along with other promising treatment schemes that have emerged in the recent months, are summarized in Table 2.

The antiparasitic agent ivermectin is another drug worth exploring further. In an in vitro study, it showed a 99.98 % reduction in viral load

S. Drożdżal, et al. Drug Resistance Updates 53 (2020) 100719

2

after 48 h of treatment (Caly et al., 2020). The drug is not toxic at a standard dose, and is safe for pregnant women, which makes it a strong candidate for evaluation in clinical trials (Caly et al., 2020). So far, one study has been established to verify its clinical efficacy, in combination with HCQ (NCT04343092) (US National Library of Medicine, 2020).

Corticosteroids

The WHO states in his recommendations that systemic steroids should not be routinely administered in treatment of viral pneumonia or acute respiratory distress syndrome (ARDS), unless recommended for other medical reasons, or as part of a clinical trial (World Health, 2020). In a systemic review of observational studies that focused on the effects of corticoid administration to patients with SARS, no clinical benefit was noted in terms of overall survival. In the case of influenza, steroid administration was associated with higher mortality rate and superimposed infections (Hui et al., 2018). General quality of evidence advocating for the use of steroids is considered weak. Another study, adjusted for confounding factors, did not present any association of steroid therapy with lower mortality rates. Finally, the latest study on steroids administration in patients with MERS, no effect on survival was disclosed, but steroids may have been responsible for halting the dis- ease progression in severe forms of LRTI. The use of steroids was as- sociated with delayed clearance of viral RNA from the respiratory tract (Arabi et al., 2018a) and blood (Lee et al., 2004). Given the evidence presently available, it is recommended to avoid the routine adminis- tration of steroids, unless recommended for the treatment of another comorbidity, e.g. shock or as continuation of treatment (Who, 2020; Russell et al., 2020).

Antibiotics

There are several studies that present potential benefits of antibiotic therapy in coronavirus infection. It is challenging to elucidate the po- tential underlying mechanism of action that might be of benefit in monotherapy, therefore most researchers turn their attention to com- bination therapy. Azithromycin, a macrolide antibiotic, in combination

with HCQ, might yield clinical benefit as an adjunctive. The insights from the French study (described in the section concerning CQ) pre- sents the thesis that azithromycin potentiates the effects of therapy (Gautret et al., 2020). Among patients treated with HCQ, 6 of them were given azithromycin (500mg initially, then 250mg per day for the next 4 days), in order to prevent superimposed bacterial infections. When comparing HCQ monotherapy to combination therapy with azi- thromycin, the percentage of patients who presented with negative PCR viral load was significantly different, at 3, 4, 5 and 6 days of follow-up, in the favor of dual therapy. On day 6, 100 % of patients were declared viral load-negative, in comparison with 57.1 % in HCQ monotherapy group and 12.5 % in control group (p < 0.001). The effect of treatment was significantly more pronounced in patients with URTI and LRTI in comparison with asymptomatic patients (p < 0.05) (Gautret et al., 2020).

Teicoplanin is a glycopeptide antibiotic routinely used in the treatment of bacterial infections. In an in vitro setting it exerts anti- SARS-CoV activity. Therefore, it might be used as one of potential therapeutic agents against COVID-19. While it is most commonly used in Gram-positive bacterial infections, especially of Staphylococcal etiology, it did present some anti-viral properties in past studies. It is effective in vitro against Ebola virus, Influenza virus, Flavivirus, Hepacivirus C (HCV), human immunodeficiency virus (HIV), and cor- onaviruses – MERS-CoV and SARS-CoV (Baron et al., 2020). In 2016, a patent application was submitted for the use of teicoplanin in MERS- CoV infection. According to Zhou et al., teicoplanin influences the early stages of viral replication cycle, inhibiting viral detachment, thereby preventing the release of viral RNA, halting further virus-cycle pro- gression (Baron et al., 2020). Latest studies carried out by the same researchers, suggested that it is likewise effective against SARS-CoV-2 (as the target sequence, the molecular target for cathepsin L is identical to that of SARS-CoV). The teicoplanin concentration that is required to inhibit viral replication by 50 % (IC50; 50 % inhibitory concentration) in vitro was 1.66 μM, a value significantly lower than that reached in human blood (8.78 μM for a daily dose of 400mg). These results require further confirmation in randomized clinical trials (Baron et al., 2020).

Fig. 1. Graphical representation of HCQ action. It is believed that most important pathways involve lysosomal enzyme stabilization, antigen presentation suppression, T-cell stimulation inhibition, or cytokine cascade blockade. HCQ inhibits the proliferation of T-cells and monocytes, and decreases the production of pro-inflammatory cytokines (Il-6, Il-17, IFN-α, IFN-λ, TNF-α). Additionally, it inhibits antibody and prostaglandin (PG) production. It decreases thrombocyte aggregation, lipid levels, insulin secretion, as well as oxi- dative stress (Nowell and Quaranta, 1985). Another mechanism that contributes to its antimalarial properties involves the inhibition of toll-like-receptors, namely TLR-3, TLR-7, and TLR-9, in response to microbial antigens that under normal conditions induce inflammatory response. Furthermore, antimalarial drugs inhibit PG production and lipid peroxidation. Decreasing PG production involves the inhibition of phospholipase A2 activity.

S. Drożdżal, et al. Drug Resistance Updates 53 (2020) 100719

3

Table 1 Summary of the clinical trials on COVID-19 treatment to date (16th of April 2020).

Therapeutic agents Clinical Trial ID Number of participants

Comments

Adalimumab ChiCTR20000 30089 60 compared to standard treatment Adamumab+Tozumab ChiCTR20000 30580 60 compared to standard treatment Anakinra NCT04341584 240 – Anakinra NCT04339712 20 compared to tocilizumab Anakinra NCT04324021 54 compared to emapalumab and standard treatment Angiotensin 1-7 NCT04332666 60 – ASC09 NCT04261270 60 compared to ritonavir; combined with oseltamivir ASC09 NCT04261907 160 compared to lopinavir/ritonavir; combined with ritonavir Atovaquone NCT04339426 25 combined with azithromycin Azithromycin NCT04341727 500 compared to chloroquine and hydroxychloroquine Azithromycin NCT04324463 1500 compared to chloroquine Azithromycin NCT04339816 240 combined with hydroxychloroquine Azithromycin NCT04336332 160 compared to hydroxychloroquine; combined with

hydroxychloroquine Azithromycin NCT04332107 2271 – Azithromycin + Hydroxychloroquine NCT04322123 630 compared to hydroxychloroquine Azithromycin + Hydroxychloroquine NCT04321278 440 compared to hydroxychloroquine Azvudine ChiCTR20000 29853 20 compared to standard treatment Azvudine ChiCTR20000 30041 40 – Azvudine ChiCTR20000 30424 30 – Azvudine ChiCTR20000 30487 10 – Baloxavir marboxil ChiCTR20000 29544 30 compared to favipiravir and standard treatment Baloxavir marboxil ChiCTR20000 29548 30 compared to favipiravir and lopinavir/ritonavir Baricitinib NCT04320277 60 – Baricitinib NCT04340232 80 – Baricitinib NCT04321993 1000 compared to hydroxychloroquine, lopinavir/ritonavir and

sarilumab BLD-2660 NCT04334460 120 – Camostat Mesylate NCT04321096 180 – CD24Fc NCT04317040 230 – CD24Fc NCT04317040 230 – Chloroquine ChiCTR20000 29542 20 compared to standard treatment Chloroquine ChiCTR20000 29609 200 compared to lopinavir/ritonavir Chloroquine ChiCTR20000 29741 112 compared to lopinavir/ritonavir Chloroquine ChiCTR20000 29826 45 – Chloroquine ChiCTR20000 29837 120 – Chloroquine ChiCTR20000 29935 100 – Chloroquine ChiCTR20000 29939 100 compared to standard treatment Chloroquine ChiCTR20000 29975 10 – Chloroquine ChiCTR20000 29988 80 compared to standard treatment Chloroquine ChiCTR20000 29992 100 compared to standard treatment; combined with

hydroxychloroquine Chloroquine ChiCTR20000 30031 120 – Chloroquine ChiCTR20000 30417 30 – Chloroquine ChiCTR20000 30718 80 compared to standard treatment Chloroquine ChiCTR20000 29898 100 compared to hydroxychloroquine Chloroquine ChiCTR20000 29899 100 compared to hydroxychloroquine Chloroquine NCT04341727 500 compared to azithromycin and hydroxychlorquine Chloroquine NCT04324463 1500 compared to azithromycin Chloroquine NCT04323527 440 – Chloroquine NCT04333628 210 compared to standard treatment Chloroquine NCT04331600 400 – Chloroquine NCT04328493 250 compared to standard treatment Ciclesonide NCT04330586 141 compared to standard treatment; combined with

hydroxychloroquine Colchicine NCT04328480 2500 – Colchicine NCT04322682 6000 – Colchicine NCT04322565 100 – CSA0001 ChiCTR20000 30939 10 – Danoprevir/Ritonavir ChiCTR20000 30000 50 compared to IFN-α, peginterferon α-2a and standard treatment Danoprevir/Ritonavir ChiCTR20000 30259 60 compared to standard treatment Danoprevir/Ritonavir ChiCTR20000 30472 20 compared to standard treatment Darunavir/Cobicistat NCT04252274 30 compared to standard treatment Darunavir/Cobicistat NCT04304053 3040 – Darunavir/Ritonavir NCT04291729 50 compared to IFN-α, lopinavir/ritonavir and peginterferon α-2a;

combined with IFN-α DAS181 NCT04324489 4 – Deferoxamine NCT04333550 50 compared to standard treatment Defibrotide NCT04335201 50 – Dexamethasone 2020-001113-21

(EU-CTR) 2000 compared to IFN β-1a and lopinavir/ritonavir

Dexamethasone NCT04327401 290 –

(continued on next page)

S. Drożdżal, et al. Drug Resistance Updates 53 (2020) 100719

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Table 1 (continued)

Therapeutic agents Clinical Trial ID Number of participants

Comments

Dihydroartemisinin/Piperaquine ChiCTR20000 30082 40 compared to IFN-α + umifenovir; combined with antiviral treatment

Ebastine ChiCTR20000 30535 100 combined with IFN-α and lopinavir Emapalumab NCT04324021 54 compared to anakinra and standard treatment Emtricitabine/Tenofovir+ Lopinavir/Ritonavir ChiCTR20000 29468 120 – Favipiravir ChiCTR20000 29544 30 compared to baloxavir marboxil and standard treatment Favipiravir ChiCTR20000 29548 30 compared to baloxavir marboxil and lopinavir/ritonavir Favipiravir ChiCTR20000 29600 90 compared to lopinavir/ritonavir; combined with IFN-α Favipiravir ChiCTR20000 29996 60 – Favipiravir ChiCTR20000 30113 20 compared to ritonavir Favipiravir ChiCTR20000 30254 240 compared to umifenovir Favipiravir ChiCTR20000 30987 150 combined with chloroquine Favipiravir JPRN

jRCTs041190120 86 –

Favipiravir NCT04273763 60 combined with bromohexine, IFN α-2b and umifenovir Favipiravir NCT04310228 150 compared to tocilizumab; combined with tocilizumab Favipiravir NCT04336904 100 – Fingolimod NCT04280588 30 compared to standard treatment Fluvoxamine NCT04342663 152 – GD31 ChiCTR20000 29895 160 – Hydroxychloroquine 2020-000890-25

(EU-CTR) 25 –

Hydroxychloroquine ChiCTR20000 29559 300 – Hydroxychloroquine ChiCTR20000 29740 78 compared to standard treatment Hydroxychloroquine ChiCTR20000 29868 200 compared to standard treatment Hydroxychloroquine ChiCTR20000 29898 100 compared to chloroquine Hydroxychloroquine ChiCTR20000 29899 100 compared to chloroquine Hydroxychloroquine ChiCTR20000 30054 100 compared to standard treatment Hydroxychloroquine NCT04261517 30 compared to standard treatment

Hydroxychloroquine NCT04315896 500 – Hydroxychloroquine NCT04315948 3100 compared to IFNβ-1a, lopinavir/ritonavir and remdesivir Hydroxychloroquine NCT04316377 202 compared to standard treatment Hydroxychloroquine NCT04342221 220 – Hydroxychloroquine NCT04340544 2700 – Hydroxychloroquine NCT04338698 500 compared to azithromycin and oseltamivir Hydroxychloroquine NCT04335552 500 compared with azithromycin, hydroxychloroquine and standard

treatment; combined with azithromycin Hydroxychloroquine NCT04334512 600 combined with azithromycin Hydroxychloroquine NCT04334382 1550 combined with azithromycin Hydroxychloroquine NCT04329832 300 combined with azithromycin Hydroxychloroquine NCT04329572 400 combined with azithromycin Hydroxychloroquine NCT04328272 75 combined with azithromycin Hydroxychloroquine NCT04323631 1116 compared to standard treatment Hydroxychloroquine NCT04321993 1000 compared to baricitinib, lopinavir/ritonavir and sarilumab Hydroxychloroquine NCT04342169 400 – Hydroxychloroquine NCT04341727 500 compared to azithromycin and chloroquine Hydroxychloroquine NCT04341493 86 compared to nitazoxanide Hydroxychloroquine NCT04334967 1250 compared to standard treatment Hydroxychloroquine NCT04333654 210 compared to standard treatment Hydroxychloroquine NCT04332991 510 – Hydroxychloroquine NCT04321616 700 compared to remdesivir and standard treatment Hydroxychloroquine+ IFN β-1b+ Lopinavir/Ritonavir IRCT20100228

003449N27 30 –

Hydroxychloroquine+ IFN β-1b+ Lopinavir/Ritonavir IRCT20100228 003449N28

30 –

Hydroxychloroquine+ Lopinavir/Ritonavir JPRN jRCTs031190227

50 –

Hydroxychloroquine+ Lopinavir/Ritonavir+ Sofosbuvir/Ledipasvir IRCT20100228 003449N29

50 –

Hydroxychlorquine+Camostat Mesylate NCT04338906 334 – IFN α-1b ChiCTR20000 29989 300 – IFN α-1b NCT04293887 328 compared to standard treatment IFN α-1b+ Lopinavir/Ritonavir+Ribavirin ChiCTR20000 29387 108 – IFN α-2b NCT04273763 60 combined with bromohexine, favipiravir and umifenovir IFN α-2b+ Lopinavir/Ritonavir ChiCTR20000 30166 20 – IFN β-1a 2020-001023-14

(EU-CTR) 400 –

IFN β-1a 2020-000936-23 (EU-CTR)

3000 compared to lopinavir/ritonavir and remdesivir

IFN β-1a 2020-001113-21 (EU-CTR)

2000 compared to dexamethasone and lopinavir/ritonavir

(continued on next page)

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Table 1 (continued)

Therapeutic agents Clinical Trial ID Number of participants

Comments

IFN β-1a NCT04343768 60 compared to hydroxychloroquine+ lopinavir / ritonavir and IFN β-1b; combined with hydroxychloroquine+ lopinavir / ritonavir

IFN β-1b NCT04343768 60 compared to hydroxychloroquine+ lopinavir / ritonavir and IFN β-1a; combined with hydroxychloroquine+ lopinavir / ritonavir

IFN β-1b+Ribavirin NCT04276688 70 combined with lopinavir/ritonavir IFN-α ChiCTR20000 29496 90 compared to lopinavir/ritonavir; combined with lopinavir/

ritonavir IFN-α ChiCTR20000 29600 90 compared to lopinavir/ritonavir and favipiravir IFN-α ChiCTR20000 29638 100 compared to rSIFN-co IFN-α ChiCTR20000 30000 50 compared to danoprevir/ritonavir, peginterferon α-2a and

standard treatment IFN-α NCT04291729 11 compared to darunavir/ritonavir, lopinavir/ritonavir and

peginterferon α-2a IFN-α and Lopinavir/Ritonavir NCT04251871 150 – IFN-α and Lopinavir/Ritonavir NCT04275388 348 – IFX-1 NCT04333420 130 compared to standard treatment Interleukin-2 ChiCTR20000 30167 80 compared to standard treatment Ivermectine NCT04343092 50 combined with Hydroxychloroquine; compared to placebo Ixekizumab ChiCTR20000 30703 40 compared to antiviral therapy; combined with antiviral therapy Leflunomide ChiCTR20000 30058 200 compared to standard treatment Leronlimab NCT04343651 70 – Levamisole NCT04

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