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Ongoing Clinical Trials for the Management of the COVID-19 Pandemic

M.P. Lythgoe, P. Middleton

PII: S0165-6147(20)30070-5 DOI: https://doi.org/10.1016/j.tips.2020.03.006 Reference: TIPS 1706

To appear in: Trends in Pharmacological Sciences

Please cite this article as: M.P. Lythgoe and P. Middleton, Ongoing Clinical Trials for the Management of the COVID-19 Pandemic, Trends in Pharmacological Sciences (2020), https://doi.org/10.1016/j.tips.2020.03.006

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© 2020 Published by Elsevier. Journal Pre-proof

Ongoing Clinical Trials for the Management of the COVID-19 Pandemic

*MP Lythgoe1 & *P Middleton2

1Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK 2 Department of Metabolism, Digestion & Reproduction, Imperial College London, St Marys Hospital, Praed Street, W21NY, London UK

*Equal contribution Corresponding Email: [email protected] Key words: Coronavirus, SARS-CoV-2, COVID-19, 2019-nCoV, pandemic

ABSTRACT

COVID-19 has rapidly developed into a worldwide pandemic causing a significant health and economic burden. There are currently no approved treatments or preventative therapeutic strategies. Hundreds of clinical studies have been registered with the intention of discovering effective treatments. This article reviews currently registered interventional clinical trials for the treatment and prevention of COVID-19 to provide an overall summary and insight into the global response. Journal Pre-proof

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RACE TOWARDS A SUCCESSFUL INTERVENTION FOR COVID-19 In the past two decades three novel pathogenic human coronaviruses have emerged from animal reservoirs [1]. These are Middle East respiratory syndrome-related coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV) and most recently severe acute respiratory syndrome coronavirus 2 (referred to as COVID-19, SARS-CoV-2 or 2019-nCoV). All three have led to global health emergencies, with significant morbidity and mortality [2]. Prior to 2020, the largest outbreak was of SARS-CoV in 2003 which affected over 8000 individuals globally and was associated with 774 deaths (case fatality rate of 9.6%)i [3]. The overall cost to the global economy of SARS-CoV was estimated to be between $30 to $100 billion[4].

Following the first identification in patients with severe in Wuhan province, in November 2019, COVID-19 has spread rapidly and now affects all permanently inhabited continents. This is the greatest pandemic of modern times and has been declared as a Public Health Emergency of International Concern by the World Health Organisation Director-Generalii. As of the 27th March 2020 (date of submission), COVID-19 affects 199 countries and territories, with over 510,000 confirmed cases globallyiii. It is associated with an estimated mortality of between 1-5%iii. Furthermore, human-to-human transmission has continued apace, despite escalating public health measures. Current estimates of the impact on the worldwide economy are $1 trillion and risingiv.

Currently there are no approved therapies for the treatment or prevention of COVID-19. With the predicted numberJournal of cases set toPre-proof rise significantly this represents a prodigious acute unmet medical need. Several national and international research groups are working collaboratively on a variety of preventative and therapeutic interventions. Potential avenues being explored include vaccine development, convalescent plasma, - based therapies, small molecule , cell-based therapies and monoclonal antibodies[5]. However, therapy development is a costly and timely process with a high attrition rate[6]. The speed of the normal drug development pathway is unacceptable in the context of the current global emergency. Therefore, there has been considerable interest in repurposing existing drugs and expediting developmental antiviral treatments, such as those for , (HBV), (HCV) and filoviruses to allow more rapid

Journal Pre-proof development[5]. The swift genomic sequencing of COVID-19 has facilitated this process, allowing comparison with MERS-CoV, SARS-CoV and other morbific viruses[7]. This strategy has identified several genomic regions of interest for therapeutic modulation, specifically the identification of highly conserved regions involving viral enzymes between different pathogenic coronaviruses.

EXPLORING CURRENT CLINICAL TRIALS FOR COVID-19 Since 2005, it has been recommended by the International Committee of Medical Journal Editors (ICMJE) that all clinical trials should be registered in publicly available domains before they may be considered for publication [8]. The introduction of this requirement and other initiatives to increase transparency have contributed to increasing number of trials being recorded in online registries such as ClinicalTrials.govv and the World Health Organizations International Clinical Trials Registry Platform (ICTRP)vi. The logging of trials on registries has vastly facilitated the dissemination of information across a number of domains including intervention, methodology, patient group and outcome measures. Furthermore, in the event of non-publication of results it means that trial information remains freely available for analysis.

In the context of the current global COVID-19 pandemic, we performed an analysis of online registries (ClinicalTrials.govv, WHO ICTRPvi, EU Clinical Trials Registervii and Cochrane Central Register of Controlled Trialsviii, Figure 1) to collate all registered therapeutic and preventative interventions under clinical investigation. We hope this will clarify current investigational advancesJournal and guide potential Pre-proof future strategies. We identified 344 interventional studies focusing on both preventative strategies, and treatment of patients infected with COVID-19 (Figure 1) as of 20th March 2020. This search identified 100 studies which focused on forms of traditional Chinese medicine (TCM), including herbal medicines, acupuncture and other forms of complementary medicine. These have not been further analysed due to lack of scientific rationale, inadequate provision of information regarding active ingredients and limited applicability to mainstream medical practice. Table 1, Key Table shows interventional treatments (Table 1A) and preventative strategies (Table 1B) under clinical investigation for COVID-19.

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TREATMENT STRATEGIES Antiviral Treatments As briefly mentioned, many studies have focused on repurposing established antiviral therapies, especially those that showed prior efficacy against SARS-CoV and MERS-CoV. Lopinavir/ combination is the most common exploratory antiviral appearing in thirty-four investigational studies (Table 1A: Antivirals). Both drugs function as protease inhibitors and are used extensively in the management of HIV-1[9]. However, lopinavir has insufficient oral for significant therapeutic activity, due to rapid catabolism by the cytochrome P450 enzyme system (specifically 3A4 isoenzyme)[9]. Thus, ritonavir is given concomitantly to inhibit this, significantly boosting the half-life of lopinavir. Lopinavir/Ritonavir was investigated for efficacy against SARS-CoV in 2004 and found to be effective when compared to historical control[10]. However, efficacy was not seen in a randomised open-label study (see Glossary) (lopinavir/ritonavir vs standard care) in 199 patients with COVID-19 (Clinical Trial Number: ChiCTR2000029308, recruitment target stated as 160 participants in the registry, Table 1). No significant benefit was seen in either overall mortality or reduction in viral load [11]. The authors highlight several limitations including a lack of treatment blinding, with study participants and investigators being aware of treatment assignments, thus reducing study objectivity. While there are multiple other ongoing studies exploring lopinavir/ritonavir in COVID-19, none utilise a double-blind methodology to address this limitation.

Remdesivir is a novel nucleotide analogue antiviral, initially developed for the management of the and MarburgJournal viruses [12,13]. HoweverPre-proof, it has efficacy against a broad range of pathogenic viruses, including both SARS-CoV and MERS-CoV in in vitro and in vivo models[12,14]. There has been much interest in this molecule, following treatment of the first COVID-19 case, and subsequent recovery in the USA[15]. There are currently ten registered trials taking place globally to investigate efficacy for COVID-19 (Table 1A: Antivirals).

Several other antiviral drugs are being investigated, predominately those with activity against various influenza subtypes and other RNA viruses. These include (T-705, Avigan,), (Arbidol), (TZV) and (Xofluza). Many

Journal Pre-proof trials are employing drugs typically used in management of RNA viruses such as HCV and HIV. These include /ritonavir, azvudine, /, sofosbuvir/, /cobicistat and Emtricitabine/Tenofovir (Table 1A: Antivirals). Additionally, there are twenty-six studies investigating the utility of antiviral interferon-based treatments, interestingly also looking at various different routes of administration (e.g. nasal).

Antimalarial Treatments Thirty-five trials are now investigating the use of the antimalarial drugs: chloroquine and hydroxychloroquine (Table 1A: Antimalarials). Chloroquine was found to have significant inhibitory effects on viral cell entry and replication in vitro [12]. An early report of clinical experience in 100 patients with COVID-19 reported both beneficial clinical and virologic outcomes with chloroquine treatment[16]. More recently, a non-randomised open label study examining the effect of hydroxychloroquine (EU Clinical Trial Numbervii: 2020-000890- 25; recruitment target stated as 25 participants in the registry) has reported on a cohort of 36 patients[17]. It has reported a significant reduction in nasopharyngeal swab viral positivity 6 days after inclusion in the hydroxychloroquine group, compared to control. However, in a deviation from their registry described protocol, 16 patients were designated as controls and 6 patients received concurrent treatment with azithromycin to prevent bacterial superinfection. Selection of patients receiving azithromycin was based on clinical judgement. The subgroup receiving azithromycin all had negative viral swabs after 6 days, in comparison to 57% (8/14) of hydroxychloroquine alone and 12.5% (2/16) of control[17]. This study is limited by itsJournal lack of randomisation Pre-proof and blinding and small sample size. There is much interest in chloroquine or hydroxychloroquine for the treatment of COVID-19 with a further thirty-four studies registered (Table 1A: Antimalarials), however only four report using a robust double-blind randomised controlled protocol to investigate efficacy.

Immunosuppressants/immunomodulators There is evidence that a hyperinflammatory response significantly contributes to mortality in COVID-19 [18]. Corticosteroids were previously trialled in SARS-CoV, however the results were inconclusive and adverse effects were associated[19]. Seven registered studies are evaluating the effect of corticosteroids in COVID-19 (Table 1A:

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Immunosuppressants). There is also interest in the anti-IL-6 drug, tocilizumab (used in treatment of rheumatoid arthritis), with seven registered trials. Other immunosuppressants being investigated include adalimumab (anti-TNF), eculizumab (anti-C5), sarilumab (anti-IL- 6), Ixekizumab (anti-17A) and fingolimod (sphingosine-1-phosphate receptor modulator, used in multiple sclerosis). Meplazumab (anti-CD147) inhibits T-cell chemotaxis but also inhibits virus cell entry[20]. A preprint of a study of 17 patients compared to 11 controls (NCT04275245, original recruitment target 20) reports improved clinical and virological outcomes[20].

Conversely, several studies are investigating immune stimulation. These include the anti- PD-1 antibody camrelizumab, recombinant IL-2, CSA0001 (LL-37 antiviral peptide with immunomodulatory functions), CD24FC (fusion protein which prevents Toll-like receptor (TLR) activation and activates immunosuppressive Siglec signalling) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) (Table 1A: Immune Modulators). Three studies (NCT04299724, NCT04276896 & ChiCTR2000030750) examine the efficacy of experimental vaccines in infected patients. Three further studies are investigating non- pharmaceutical interventions to modulate the immune system using cytokine filtration devices such as oXiris and CytoSorb to reduce circulating cytokines and inflammatory mediators (Table 1A: Cytokine Removal).

Cell & Plasma based Therapy Twenty-four registered studies plan to investigate the role of mesenchymal stem cells (MSCs) (Table 1A: Cell BasedJournal Therapies). MSC Pre-proofs have immunomodulatory and tissue repair effects through the secretion of cytokines and growth factors. They have previously been examined in a phase 1 trial in Adult Respiratory Distress Syndrome (ARDS)[21]. As most of the deaths in COVID-19 are from respiratory failure, MSCs are postulated to have a beneficial effect. So far, one study of MSCs (ChiCTR2000029990, recruitment target stated as 120 participants in the registry) has reported results in 7 patients with COVID-19, showing improvement in both clinical and inflammatory outcome compared to 3 control patients treated with saline [22]. This study plans to recruit 120 participants with 60 patients in both the treatment (MSC) and control (saline) arms.

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Use of plasma from patients who have recovered from COVID-19 has the potential benefit of providing disease specific neutralising antibodies, before targeted therapies can be developed. During the Ebola outbreak in 2014, the WHO advised the use of convalescent plasma or whole blood therapies. However, a non-randomized comparative study in 84 patients with Ebola found no associated improvement in survival [23]. There are currently twelve registered trials to investigate convalescent plasma or immunoglobulins in COVID-19 (Table 1A: Plasma Based Therapies).

Alternative treatment strategies Various other treatment strategies are currently under investigation which include the anti- fibrotic/inflammatory agent pirfenidone (used in treatment of idiopathic pulmonary fibrosis), and the anti-angiogenic agents: bevacizumab (anti-VEGF) and thalidomide (Table 1A: Antifibrotics & Antiangiogenics). A further five studies are aimed at assessing the therapeutic utility of modifying the gut microbiome (Table 1A: Microbiome), though the mechanisms by which this is performed are not explicit in the trial registers. Ten other studies are investigating holistic approaches including physiotherapy, psychology and nutritional intervention on disease outcome (Table 1A: Therapy Interventions).

PREVENTATIVE STRATEGIES No effective vaccine or antiviral therapeutic agent for post-exposure prophylaxis has been approved for preventing COVID-19 or any other human coronavirus. The development of vaccines is a complex time-consuming process with a high attrition rate. Success in generating aJournal vaccine in the recent Pre-proof 2009 flu pandemic (H1N1/09) has fuelled optimism towards one for COVID-19[24]. Furthermore, both the rapid genomic sequencing of COVID-19 and insights gleaned during vaccine exploration for both MERS-CoV and SARS- CoV (both terminated due to successful disease containment) has allowed pre-clinical and animal work to advance rapidly[7].

Over 50 novel vaccines are estimated to be in development, however currently only three vaccine studies are registered for phase 1 evaluation (Table 1B: Vaccines). Two studies are actively recruiting in the USA and China, and a further study is newly registered (initial set up). A modified mRNA vaccine (mRNA-1273) that encodes COVID-19 viral spike protein has

Journal Pre-proof progressed rapidly through pre-clinical development to human testing (42 days from sequence identification) by Moderna, Inc and the National Institute of and Infectious Diseases (NIAID). However, such rapid development has prompted safety concerns in some experienced virologists[25]. Other current investigational vaccines being tested in humans include a replicative-defective adenovirus type 5 (Ad5)-nCoV that expresses COVID-19 viral proteins and a lentiviral vector system to express viral proteins and immunomodulatory genes to modify antigen presenting cells (aAPC) (Table 1B: Vaccines).

Furthermore, post exposure prophylaxis is an attractive strategy for both healthcare workers and household contacts exposed to COVID-19. Currently six studies are looking at use of antivirals, such as umifenovir, antimalarials such as hydroxychloroquine and chloroquine and the use of recombinant human interferon a1b spray for prevention of infection (Table 1B: Antiviral & Antimalarial).

GLOBAL RESPONSE Over 85% of the clinical trials (excluding TCM) for either prevention and/or treatment of COVID-19 have been registered in China, which is not surprising given that the country saw the outbreak of the disease first. The first clinical trials were registered within one month of COVID-19 identification and rapidly expanded after that (Figure 2). Public health initiatives have thus far successfully curtailed the previously exponential growth of COVID-19 cases in China. This has reduced the number of potential participants for clinical trials in China and the registration of new clinical trials has since declined. Furthermore, a number of studies have also been withdrawnJournal or suspended Pre-proof for example, NCT04293692 and ChiCTR2000030082.

The wider global community has been slower to react. The first case of COVID-19 outside of Asia was reported in late Januaryiii. Subsequently the incidence of COVID-19 has increased dramatically. The World Health Organization has now declared that Europe has become the new disease epicentre, with 40% of total cases and risingix. However, until recently less than 5% of clinical trials for COVID-19 have been registered in Europe (Figure 2). The rapid escalation of trial registrations in response to increasing disease incidence seen in China has unfortunately not occurred in Europe. Despite this, there are now encouraging signs.

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Initiatives focused on pan-European collaboration are being championed by the European Union with a priority on larger patient studies, than seen in the smaller studies registered in Chinax. Consequently, the median number of participants in European registered studies is 1200 participants, in comparison to 60 and 394 in China and USA respectively. An example is NCT04303507 (chloroquine post-exposure prophylaxis) which plans to recruit 10,000 participants (Table 1B). However, this may in part reflect a higher proportion of preventative studies currently being carried out which include large numbers of participants. Hopefully larger studies will provide higher quality evidence, although may take longer to generate results in the context of this escalating public health crisis.

With an increasing number of COVID-19 cases reported in North America, there has also been an increase in clinical trial registrations in the USA. The NIAID registered the first USA- led global trial in mid-February utilising 50 sites across Asia and USA (Figure 2). Studies registered in the USA have generally placed an emphasis on larger participant numbers than China (see Table 1) and adaptive trial design for both treatment and prevention of COVID- 19.

CONCLUDING REMARKS The COVID-19 pandemic represents the gravest global public health threat seen since the 1918 influenza outbreak and has rapidly become a global healthcare emergency. Clinical trials need to produce high quality data which can be used to objectively assess potentials therapies for both treatment and prevention of this global emergency. It is imperative to plough international resourcesJournal into high quality Pre-proof design clinical trials with robust scientific rationale and vigorous statistical rigor. Increasing international collaboration and the globalisation of clinical trials with large patient numbers should be the way forward to give significant and definitive results.

DISCLAIMER STATEMENT: MP Lythgoe has received an educational travel grant from Bayer. P Middleton has nothing to declare.

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RESOURCES:

i) https://www.who.int/csr/sars/country/table2004_04_21/en/ ii) http://www.euro.who.int/en/health-topics/health-emergencies/coronavirus-covid-19 iii) https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports iv) https://unctad.org/en/pages/newsdetails.aspx?OriginalVersionID=2300 v) https://clinicaltrials.gov vi) https://www.who.int/ictrp/en/ vii) https://www.clinicaltrialsregister.eu/ viii) https://www.cochranelibrary.com/central/about-central ix) http://www.euro.who.int/en/health-topics/health-emergencies/coronavirus-covid- 19/news/news/2020/3/global-solidarity-across-countries-and-continents-needed-to- fight-covid-19 x) https://www.bioworld.com/articles/433824-eu-boosts-funding-for-covid-19-epidemic- encourages-clinical-trial-cooperation xi) https://www.isrctn.com/?gclid=Cj0KCQjwjoH0BRD6ARIsAEWO9Dt7ppI5xmcUMgabefiiR nPVSbsoH3CtwieB5maS2z4gzAyZ1nNjd8MaAjEREALw_wcB

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20 Bian, H. et al. (2020) Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial. medRxiv DOI: 10.1101/2020.03.21.20040691 21 Wilson, J.G. et al. (2015) Mesenchymal stem (stromal) cells for treatment of ARDS: A phase 1 clinical trial. The Lancet Respiratory Medicine 3, 24–32 22 Leng, Z. et al. (2020) Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia. Aging and disease 11, 216 23 van Griensven, J. et al. (2016) Evaluation of convalescent plasma for Ebola virus disease in Guinea. New England Journal of Medicine 374, 33–42 24 Chen, Z. et al. (2010) Generation of Live Attenuated Novel Influenza Virus A/California/7/09 (H1N1) Vaccines with High Yield in Embryonated Chicken Eggs. Journal of Virology 84, 44–51 25 Jiang, S. (2020) Don’t rush to deploy COVID-19 vaccines and drugs without sufficient safety guarantees. Nature 579, 321

TABLE Table 1, Key Table: Ongoing Clinical Trials for treatment (A) and prevention (B) of COVID-19 (current as of March 20th, 2020)

Table 1A: Ongoing Clinical Trials for Treatment of COVID-19

Clinical Intervention SizeA Randomised Blinded Status Country Trial ID of Origin (Registry) (Pharma Sponsor)

Antiviral ChiCTR20000 Arm A (Mild-moderate): 205 No No Recruiting China 29609 Chloroquine (ICTPR) Arm B (Mild-moderate): Lopinavir/Ritonavir Arm C (Mild-moderate): Lopinavir/Ritonavir + ChloroquineJournal Pre-proof Arm D (Severe): Lopinavir/Ritonavir Arm E (Severe): Chloroquine ChiCTR20000 Arm A: alpha-interferon 90 No No Recruiting China 29600 atomization (ICTPR) Arm B Lopinavir/Ritonavir & alpha-interferon atomization Arm C: Favipiravir & alpha-interferon atomization

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NCT04261270 Arm A: ASC09 & 60 Yes Single Recruiting China (ClinicalTrials. gov) Arm B: Ritonavir & Oseltamivir Arm C: Oseltamivir NCT04261907 Arm A: ASC09/Ritonavir 160 Yes No Recruiting China (ClinicalTrials. Arm B: (Ascletis gov) Lopinavir/Ritonavir Pharm) ChiCTR20000 Arm A: Azvudine 10 No No Recruiting China 30487 (ICTPR) ChiCTR20000 Arm A: Azvudine 30 No No Not China 30424 Recruiting (ICTPR) ChiCTR20000 Arm A: Azvudine 40 No No Not China 30041 Recruiting (ICTPR) ChiCTR20000 Arm A: Azvudine 20 Yes No Recruiting China 29853 Arm B: Standard (ICTPR) Treatment ChiCTR20000 Arm A: Baloxavir 30 Yes Uns. Not China 29544 Marboxil Recruiting (ICTPR) Arm B: Favipiravir Arm C: Standard Treatment

ChiCTR20000 Arm A: Baloxavir 30 Yes No Not China 29548 Marboxil Recruiting (ICTPR) Arm B: Favipiravir Arm C: Lopinavir/Ritonavir ChiCTR20000 Arm A: Basic Treatment 240 Yes Yes Recruiting China 30001 + Triazavirin (ICTPR) Arm B: Basic Treatment NCT04273763 Arm A: Bromhexine 60 Yes No Recruiting China (ClinicalTrials. (mucolytic) & (WanBan gov) Umifenovir & Interferon gDe a2b & Favipiravir Pharm. Arm B: UmifenovirJournal & Pre-proof Group) Interferon a2b ChiCTR20000 Arm A: Conventional 60 Yes No Recruiting China 30002 treatment (ICTPR) Arm B: Conventional treatment + tranilast ChiCTR20000 Arm A: 20 Unspecified No Recruiting China 30472 Danoprevir/Ritonavir (ICTPR) Arm B: Standard Treatment ChiCTR20000 Arm A: 60 Yes Uns. Recruiting China 30259 Danoprevir/Ritonavir (ICTPR) Arm B: Standard Treatment

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ChiCTR20000 Arm A: 50 Unspecified No Recruiting China 30000 Danoprevir/Ritonavir (ICTPR) Arm B: Pegasys Arm C: Novaferon Arm D: Coriolus Arm E: Standard Treatment NCT04252274 Arm A: Darunavir & 30 Yes No Recruiting China (ClinicalTrials. Cobicistat gov) Arm B: Standard Treatment NCT04304053 Arm A: 3040 Yes No Recruiting Spain (ClinicalTrials. Darunavir/Cobicistat gov) Arm B: Isolation ChiCTR20000 Arm A: 100 Yes No Not China 29541 Darunavir/Cobicistat & Recruiting (ICTPR) Thymosin Arm B: Lopinavir/Ritonavir & Thymosin Arm C: Thymosin NCT04291729 Arm A: 50 No No Recruiting China (ClinicalTrials. Darunavir/ritonavir & (Ascletis gov) atomized interferon Pharmace Arm B: Peginterferon utical) alfa 2 Arm C: Interferon alfa (Novaferon) Arm D: Lopinavir/Ritonavir Arm E: Atomized interferon + Chinese medicine ( Uns.) ChiCTR20000 Arm A: Ebastine & 100 Yes Single Recruiting China 30535 Interferon alpha (ICTPR) inhalation & Lopinavir Arm B: InterferonJournal alpha Pre-proof inhalation & Lopinavir ChiCTR20000 Arm A: Favipiravir 20 Yes No Recruiting China 30113 Arm B: Ritonavir (ICTPR) ChiCTR20000 Arm A: Favipiravir 240 Yes No Recruiting China 30254 Arm B: Umifenovir (ICTPR)

ChiCTR20000 Arm A: Favipiravir & 150 Yes Uns. Recruiting China 30987 Chloroquine (ICTPR) Arm B: Favipiravir Arm C: Placebo NCT04310228 Arm A: Favipiravir & 150 Yes No Recruiting China (ClinicalTrials. Tocilizumab gov) Arm B: Favipiravir Arm C: Tocilizumab

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ChiCTR20000 Arm A: GD31 160 No Uns. Recruiting China 29895 (ICTPR) IRCT20100228 Arm A: 30 Yes No Recruiting Iran 003449N27 Hydroxychloroquine & (ICTPR) Lopinavir/Ritonavir & Interferon beta-1b Arm B: Hydroxychloroquine & Lopinavir/Ritonavir IRCT20100228 Arm A: 30 Yes No Recruiting Iran 003449N28 Hydroxychloroquine & (ICTPR) Lopinavir/Ritonavir & Interferon beta-1a Arm B: Hydroxychloroquine & Lopinavir/Ritonavir IRCT20100228 Arm A: 50 Yes No Recruiting Iran 003449N29 Hydroxychloroquine & (ICTPR) Lopinavir/Ritonavir & Sofosbuvir/Ledipasvir Arm B: Hydroxychloroquine & Lopinavir/Ritonavir JPRN- Arm A: Immediate 86 Yes No Recruiting Japan jRCTs0411901 Favipiravir (Day 1 – 10) 20 (ICTPR) Arm B: Delayed Favipiravir (D6-15) 2020-001023- Arm A: Inhaled 400 Yes Double Recruiting UK 14 Interferon b-1a (Synairge (EU-CTR) Arm B: Placebo n Ltd) ChiCTR20000 Arm A: Interferon a1b 300 Yes Uns. Not China 29989 eye drops Recruiting (ICTPR) Arm B: Placebo eye drops NCT04293887 Arm A: Interferon alpha 328 Yes No Not China (ClinicalTrials. 1b nebulisedJournal Pre-proof Recruiting gov) Arm B: Standard Treatment

ChiCTR20000 Arm A: Interferon 30 Yes Uns. Recruiting China 30922 alpha-2a & (ICTPR) Arm B: Umifenovir & Ribavirin ChiCTR20000 Arm A: 160 Yes No Recruiting China 29308 Lopinavir/Ritonavir (ICTPR) [11] Arm B Standard Treatment NCT04307693 Arm A: 150 Yes No Recruiting South (ClinicalTrials. Lopinavir/Ritonavir Korea gov) Arm B:

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Hydroxychloroquine Arm C: No intervention ChiCTR20000 Arm A: 60 Yes Uns. Recruiting China 30187 Lopinavir/Ritonavir (ICTPR) Arm B: Standard of Care

2020-001113- Arm A: 2000 Yes No Recruiting UK 21 Lopinavir/Ritonavir (EU-CTR) Arm B: Dexamethasone Arm C: Interferon beta- 1a Arm D: Placebo 2020-000936- Arm A: 3000 Yes No Recruiting France 23 Lopinavir/Ritonavir (EU-CTR) Arm B: Interferon beta- 1a Arm C: Remdesivir NCT04251871 Arm A: 150 Yes No Recruiting China (ClinicalTrials. Lopinavir/Ritonavir & gov) alpha-interferon inhalation & Traditional Chinese Medicine Arm B: Lopinavir/Ritonavir & alpha-interferon inhalation ChiCTR20000 Arm A: 120 Unspecified Uns. Not China 29468 Lopinavir/Ritonavir & Recruiting (ICTPR) Emtricitabine/ Tenofovir Arm B: Lopinavir/Ritonavir JPRN- Arm A: 50 Unspecified Uns. Not Japan jRCTs0311902 Lopinavir/Ritonavir & Recruiting 27 (ICTPR) Hydroxychloroquine ChiCTR20000 Arm A: 20 Yes No Not China 30166 Lopinavir/RitonavirJournal & Pre-proof Recruiting (ICTPR) interferon alpha 2b & Qing-Wen Bai-Du-Yin granules Arm B: Lopinavir/Ritonavir & interferon alpha 2b ChiCTR20000 Arm A: 80 Unspecified Uns. Recruiting China 30218 Lopinavir/Ritonavir & (ICTPR) Xiyanping Injection Arm B: Ritonavir

NCT04252885 Arm A: 125 Yes No Recruiting China (ClinicalTrials. Lopinavir/Ritonavir + gov) Basic treatment (Uns.)

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Arm B: Umifenovir + Basic treatment (Uns.) Arm C: Basic treatment (Uns.) NCT04276688 Arm A: 70 Yes No Recruiting Hong (ClinicalTrials. Lopinavir/Ritonavir + Kong gov) Ribavirin + Interferon beta-1b Arm B: Lopinavir/Ritonavir ChiCTR20000 Arm A: 328 Yes No Recruiting China 29539 Lopinavir/Ritonavir (ICTPR) Arm B: Standard Treatment

ChiCTR20000 Arm A: Low dose 60 Yes No Recruiting China 29996 Favipiravir (ICTPR) Arm B: Medium dose Favipiravir Arm C: High dose Favipiravir ChiCTR20000 Arm A: Nebulised rSIFN- 100 Yes Yes Recruiting China 29638 co (ICTPR) Arm B: Nebulised Interferon-alfa ChiCTR20000 Arm A: Novaferon 90 Yes No Recruiting China 29496 Atomization inhalation (ICTPR) Arm B: Lopinavir/ritonavir Arm C: Novaferon & Lopinavir/Ritonavir NCT04303299 Arm A: Oseltamivir & 80 Yes No Not Thailand (ClinicalTrials. Chloroquine Recruiting gov) Arm B: Lopinavir/Ritonavir & Favipiravir Arm C: Journal Pre-proof Lopinavir/Ritonavir & Oseltamivir Arm D: Lopinavir/Ritonavir & Oseltamivir Arm E: Favipiravir & Lopinavir/Ritonavir Arm F: Darunavir/Ritonavir & Oseltamivir & Chloroquine Arm G: Standard Treatment NCT04302766 Arm A: Remdesivir Unspe Unspecified Unspeci Available USA (ClinicalTrials.

Journal Pre-proof

gov) cified fied NCT04292899 Arm A: Remdesivir 400 Yes No Recruiting USA & (ClinicalTrials. Arm B: Standard Asia gov) Treatment (Gilead) NCT04292730 Arm A: Remdesivir 600 Yes No Recruiting US & Asia (ClinicalTrials. Arm B: Standard (Gilead) gov) Treatment

NCT04280705 Arm A: Remdesivir 394 Yes Double Recruiting USA (ClinicalTrials. Arm B: Placebo South gov) Korea 2020-000841- Arm A: Remdesivir 400 Yes No Recruiting Worldwid 15 Arm B: Standard e (EU-CTR) Treatment (Gilead)

2020-000842- Arm A: Remdesivir 600 Yes No Recruiting Worldwid 32 Arm B: Standard e (EU-CTR) Treatment (Gilead)

NCT04252664 Arm A: Remdesivir 308 Yes Quadru Recruiting China (ClinicalTrials. Arm B: Placebo ple gov) NCT04257656 Arm A: Remdesivir 453 Yes Quadru Recruiting China (ClinicalTrials. Arm B: Placebo ple gov) NCT04315948 Arm A: Remdesivir 3100 Yes No Recruiting France (ClinicalTrials. Arm B: gov) Lopinavir/Ritonavir Arm C: Lopinavir/Ritonavir & Interferon beta-1a Arm D: Hydroxychloroquine Arm E: Standard Treatment ChiCTR20000 Arm A: Ribavirin & 108 Unspecified Unspeci Recruiting China 29387 Interferon alpha-1b fied (ICTPR) Arm B: Journal Pre-proof Lopinavir/Ritonavir & Interferon alpha-1b Arm C: Ribavirin & Lopinavir/Ritonavir & Interferon alpha-1b IRCT20200128 Arm A: Sofosbuvir/ 70 Yes Single Recruiting Iran 046294N2 Daclatasvir (ICTPR) Arm B: Standard Treatment ChiCTR20000 Arm A: Traditional 60 Unspecified Unspeci Recruiting China 29400 Chinese Medicine fied (ICTPR) Arm B: Lopinavir/Ritonavir Arm C: Traditional

Journal Pre-proof

Chinese Medicine & Lopinavir/Ritonavir

ChiCTR20000 Arm A: Type 1 30 Yes Unspeci Recruiting China 30262 Interferon & TFF2 Dose fied (ICTPR) 1 Arm B Type 1 Interferon & TFF2 Dose 2 Arm C: Standard Treatment ChiCTR20000 Arm A: Umifenovir 480 Yes No Not China 29573 Arm B: Novaferon & Recruiting (ICTPR) Umifenovir Arm C: Lopinavir/Ritonavir Arm D: Umifenovir Arm E: Novaferon & Lopinavir/Ritonavir Arm F: Novaferon & Umifenovir

ChiCTR20000 Arm A: Umifenovir 380 Yes No Recruiting China 29621 Arm B: Standard (ICTPR) Treatment NCT04254874 Arm A: Umifenovir 100 Yes Single Recruiting China (ClinicalTrials. Arm B: Umifenovir & gov) pegylated Interferon a2b

NCT04255017 Arm A: Umifenovir 400 Yes Single Recruiting China (ClinicalTrials. Arm B: Oseltamivir gov) Arm C: Lopinavir/Ritonavir ChiCTR20000 Arm A: Umifenovir & 40 Yes No Recruiting China 29993 Liushen capsule (ICTPR) Arm B: Standard Treatment Journal Pre-proof NCT04275388 Arm A: Xiyanping 348 Yes No Not China (ClinicalTrials. injection & Recruiting (Jiangxi gov) Lopinavir/Ritonavir & Qingfeng alpha-interferon Pharmace nebulization utical) Arm B: Lopinavir/Ritonavir & Alpha-interferon nebulization

Antimalarial ChiCTR20000 Arm A: Chloroquine 120 Yes Double Recruiting China 30031 Arm B: Placebo (ICTPR)

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ChiCTR20000 Arm A: Chloroquine 80 Uns. Uns. Recruiting China 29988 Arm B: Standard (ICTPR) Treatment ChiCTR20000 Arm A: Chloroquine 10 No Unspeci Not China 29975 fied Recruiting (ICTPR) ChiCTR20000 Arm A: Chloroquine 100 Yes Single Recruiting China 29939 Arm B: Standard (ICTPR) Treatment ChiCTR20000 Arm A: Chloroquine 100 No Unspeci Recruiting China 29935 fied (ICTPR) ChiCTR20000 Arm A: Chloroquine 120 Yes Double Not China 29837 Arm B: Placebo Recruiting (ICTPR) ChiCTR20000 Arm A: Chloroquine 45 Yes Double Not China 29826 Arm B: Placebo Recruiting (ICTPR) ChiCTR20000 Arm A: Chloroquine 20 Unspecified Uns. Recruiting China 29542 Arm B: Standard (ICTPR) Treatment ChiCTR20000 Arm A: Chloroquine 112 Yes No Recruiting China 29741 Arm B: (ICTPR) Lopinavir/Ritonavir ChiCTR20000 Arm A: Chloroquine 80 Yes No Recruiting China 30718 Arm B: Standard (ICTPR) Treatment ChiCTR20000 Arm A: Chloroquine & 100 Yes No Not China 29992 Hydroxychloroquine Recruiting (ICTPR) Arm B: Standard Treatment ChiCTR20000 Arm A: Chloroquine 30 Unspecified Unspeci Not China 30417 aerosol inhalation fied Recruiting (ICTPR) Arm B Water aerosol inhalation ChiCTR20000 Arm A: 40 Yes No Suspended China 30082 Dihydroartemisinin/ (ICTPR) piperaquine tablets combined withJournal antiviral Pre-proof treatment (presumed Alfa-interferon + Umifenovir Arm B: Alfa-interferon + Umifenovir

ChiCTR20000 Arm A: 100 Yes No Recruiting China 29898 Hydroxychloroquine (ICTPR) Arm B: Chloroquine NCT04261517 Arm A: 30 Yes No Recruiting China (ClinicalTrials. Hydroxychloroquine gov) Arm B: Standard of Care ChiCTR20000 Arm A: 100 Yes No Not China 30054 Hydroxychloroquine Recruiting (ICTPR)

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Arm B: Standard Treatment

ChiCTR20000 Arm A: 200 Yes Uns. Recruiting China 29868 Hydroxychloroquine (ICTPR) Arm B: Standard Treatment

ChiCTR20000 Arm A: 78 Yes No Recruiting China 29740 Hydroxychloroquine (ICTPR) Arm B: Standard Treatment ChiCTR20000 Arm A: 300 Unspecified Unspeci Recruiting China 29559 Hydroxychloroquine fied (ICTPR) Arm B: Hydroxychloroquine Arm C: Placebo 2020-000890- Arm A: 25 No No Recruiting France 25 Hydroxychloroquine (EU-CTR) [17] ChiCTR20000 Arm A: 100 Yes No Recruiting China 29899 Hydroxychloroquine (ICTPR) Arm B: Chloroquine

NCT04315896 Arm A: 500 Yes Quadru Not Mexico (ClinicalTrials. Hydroxychloroquine ple Recruiting gov) Arm B: Placebo NCT04316377 Arm A: 202 Yes No Not Norway (ClinicalTrials. Hydroxychloroquine Recruiting gov) Arm B: Standard Treatment Immunosuppressants NCT04263402 Arm A: 100 Yes Single Recruiting China (ClinicalTrials. Methylprednisolone gov) (<40mg/d) Arm B: MethylprednisoloneJournal Pre-proof (40-80mg/d) ChiCTR20000 Arm A: Conventional 60 Yes No Not yet China 30089 treatment + recruiting (ICTPR) adalimumab Arm B: Conventional treatment

ChiCTR20000 Arm A: Early 200 Yes No Recruiting China 30481 corticosteroid (ICTPR) intervention Arm B: Middle-late corticosteroid intervention Arm C: Standard Care

Journal Pre-proof

NCT04288713 Arm A: Eculizumab Unspecified Unspeci Available USA (ClinicalTrials. Unspe fied gov) cified NCT04280588 Arm A: Fingolimod 30 No No Recruiting China (ClinicalTrials. Arm B: Standard gov) Treatment ChiCTR20000 Arm A: Ixekizumab & 40 Yes Single Recruiting China 30703 antiviral therapy (ICTPR) Arm B: Antiviral Therapy NCT04275245 Arm A: Meplazumab 20 No No Recruiting China (ClinicalTrials. gov) [20] NCT04273321 Arm A: 400 Yes No Recruiting China (ClinicalTrials. Methylprednisolone gov) Arm B: Standard Treatment NCT04244591 Arm A: 80 Yes No Recruiting China (ClinicalTrials. Methylprednisolone gov) Arm B: Standard Treatment ChiCTR20000 Arm A: 100 Yes No Not China 29656 Methylprednisolone Recruiting (ICTPR) Arm B: Standard Treatment ChiCTR20000 Arm A: 48 Yes Unspeci Recruiting China 29386 Methylprednisolone fied (ICTPR) Arm B: Standard Treatment NCT04315298 Arm A: Sarilumab high 400 Yes Quadru Recruiting USA (ClinicalTrials. dose ple (Regener gov) Arm B: Sarilumab low on Pham.) dose Arm C: Placebo ChiCTR20000 Arm A: Standard 200 Yes Yes Not yet China 30058 Treatment + recruiting (ICTPR) leflunomide Arm B: StandardJournal Pre-proof Treatment + placebo ChiCTR20000 Arm A: Tocilizumab 60 No No Not China 30196 Recruiting (ICTPR) ChiCTR20000 Arm A: Tocilizumab 188 Yes Unspeci Recruiting China 29765 Arm B: Standard fied (ICTPR) Treatment NCT04315480 Arm A: Tocilizumab 30 No No Not France (ClinicalTrials. Recruiting gov) NCT04317092 Arm A: Tocilizumab 330 No No Recruiting Italy (ClinicalTrials. gov) ChiCTR20000 Arm A: Tocilizumab, 100 No Unspeci Not China 30442 IVIG & CCRT fied Recruiting (ICTPR)

Journal Pre-proof

ChiCTR20000 Arm A: TozumabB & 60 Yes Unspeci Recruiting China 30580 Adalimumab fied (ICTPR) Arm B: Standard Treatment Immune Modulators NCT04317040 Arm A: CD24Fc 230 Yes Quadru Not USA (ClinicalTrials. Arm B: Placebo ple Recruiting (OncoIm gov) mune) ChiCTR20000 Arm A: Conventional 40 Yes No Recruiting China 29776 treatment + (ICTPR) polyinosinic- polycytidylic acid Arm B: Conventional treatment NCT04299724 Arm A: Covid-19/aAPC 100 No No Recruiting China (ICTPR) vaccine ChiCTR20000 Arm A: CSA0001 10 Yes Unspeci Recruiting China 30939 fied (ICTPR) ChiCTR20000 Arm A: Inhaled inactive 60 Yes Yes Recruiting China 30016 mycobacterium vaccine (ICTPR) Arm B: Inhaled physiological saline ChiCTR20000 Arm A: Interleukin-2 80 Yes Unspeci Not China 30167 Arm B: Standard fied Recruiting (ICTPR) Treatment NCT04261426 Arm A: IVIG 80 Yes No Not China (ClinicalTrials. Arm B: Standard Recruiting gov) Treatment NCT04276896 Arm A: LV-SMENP-DC 100 No No Recruiting China (ICTPR) Vaccine and antigen

specific cytotoxic T cells NCT04268537 Arm A: PD-1 blocking 120 Yes Single Not China (ClinicalTrials. Ab Recruiting gov) Arm B: Thymosin Arm C: Standard Treatment Journal Pre-proof ChiCTR20000 Arm A: PD-1 40 Yes No Not yet China 30028 monoclonal Antibody + recruiting (ICTPR) Standard Treatment Arm B: Standard Treatment NCT04312997 Arm A: PUL-042 100 Yes Quadru Not USA (ClinicalTrials. nebuliser ple Recruiting (Pulmotec gov) Arm B: Sterile saline t) inhaler ChiCTR20000 Arm A: Recombinant 120 Yes Unspeci Not China 30750 Chimeric DC Vaccine fied Recruiting (ICTPR) Arm B: Normal Saline ChiCTR20000 Arm A: Standard 200 Yes No Not yet China 30007 treatment + rhG-CSF recruiting (ICTPR)

Journal Pre-proof

Arm B: Standard treatment ChiCTR20000 Arm A: Standard 40 No No Recruiting China 29636 treatment and vMIP (ICTPR) atomized inhalation

ChiCTR20000 Arm A: Subcutaneous 120 Yes No Recruiting China 29806 Thymosin (ICTPR) Arm B: Camrelizumab infusion Arm C: Conventional treatment

ChiCTR20000 Arm A: Ulinastatin 100 Yes No Recruiting China 30779 () (ICTPR) Arm B: Standard Treatment Cytokine Removal ChiCTR20000 Arm A: CytoSorb 19 No No Not China 30475 cytokine removal Recruiting (ICTPR) ChiCTR20000 Arm A: oXiris 19 No No Not China 30477 membrane Recruiting (ICTPR) ChiCTR20000 Arm A: oXiris 30 Unspecified Unspeci Not China 30265 membrane fied Recruiting (ICTPR) Arm B: Standard Treatment Cell Based Therapy ChiCTR20000 Arm A: High dose MSCs 20 No Uns. Recruiting China 30835 Arm B: Low dose MSCs (ICTPR) ChiCTR20000 Arm A: High dose NK 60 Unspecified Unspeci Not China 29817 Cells & MSCs fied Recruiting (Guangch (ICTPR) Arm B: Conventional ou reborn dose NK cells & MSCs health Arm C: Preventive dose managem NK cells and JournalMSCs Pre-proof ent co)

ChiCTR20000 Arm A: Menstrual 73 Unspecified Unspeci Recruiting China 29606 Blood-derived Stem fied (ICTPR) cells Arm B: Artificial liver therapy Arm C: Artificial liver therapy & Menstrual blood-derived Stem Cells Arm D: Standard Treatment NCT04315987 Arm A: MSCs 24 No No Not Brazil (ClinicalTrials. Recruiting (Cellavita gov)

Journal Pre-proof

Pesquisa Cientifica Ltd) NCT04276987 Arm A: MSC derived 30 No No Not China (ClinicalTrials. exosomes Recruiting (Cellular gov) Biomedici ne Group) NCT04288102 Arm A: MSCs 60 Yes Quadru Recruiting China (ClinicalTrials. Arm B: Placebo ple gov)

NCT04252118 Arm A: MSCs 20 No No Recruiting China (ClinicalTrials. Arm B: Standard (IPM, gov) Treatment Vcanbio Cell & Gene Engineeri ng) ChiCTR20000 Arm A: MSCs 9 No Unspeci Recruiting China 30300 fied (ICTPR) ChiCTR20000 Arm A: MSCs 32 Unspecified Unspeci Not China 30224 Arm B: Normal Saline fied Recruiting (ICTPR) ChiCTR20000 Arm A: MSCs 60 Unspecified Unspeci Not China 30173 Arm B: Standard fied Recruiting (Hunan (ICTPR) Treatment yuanpin Cell Biotech) ChiCTR20000 Arm A: MSCs 20 No No Recruiting China 30020 (ICTPR) ChiCTR20000 Arm A: MSCs 120 Yes Unspeci Recruiting China 29990 Arm B: Saline fied (ICTPR) [22] ChiCTR20000 Arm A: MSCs derived 26 Unspecified Unspeci Not China 30261 exosomes fied Recruiting (ICTPR) Arm B: Standard Treatment NCT04280224 Arm A: NK CellsJournal 30 Pre-proofYes No Recruiting China (ClinicalTrials. Arm B: Standard gov) Treatment ChiCTR20000 Arm A: NK cells 40 Unspecified Unspeci Not China 30509 Arm B: Electrolyte fied Recruiting (ICTPR) Injection ChiCTR20000 Arm A: NK cells and 20 Yes No Not China 30944 MSC Recruiting (ICTPR) Arm B: Standard Treatment NCT04302519 Arm A: Pulp MSCs 24 No No Not China (ClinicalTrials. Recruiting (CAR-T gov) Biotechno logy Co., Ltd.)

Journal Pre-proof

ChiCTR20000 Arm A: Ruxolitinib & 70 Yes Single Recruiting China 29580 MSCs (ICTPR) Arm B: Standard Treatment

NCT04299152 Arm A: Stem Cell 20 Yes Single Not USA (ClinicalTrials. Educator Therapy Recruiting (Tianhe gov) Arm B: Standard Stem Cell Treatment Biotechno logies Inc) ChiCTR20000 Arm A: Umbilical Cord 90 Unspecified Unspeci Not China 30329 blood CIK cells fied Recruiting (ICTPR) Arm B Umbilical Cord NK cells Arm C: Standard Treatment ChiCTR20000 Arm A: Umbilical Cord 60 Unspecified Unspeci Not China 29812 Blood Mononuclear Cell fied Recruiting (Guangzh (ICTPR) Preparations ou reborn Arm B: Standard health Treatment managem ent consultati on co) ChiCTR20000 Arm A: Umbilical Cord 30 Yes Unspeci Recruiting China 29572 Blood Mononuclear fied (ICTPR) Cells Arm B: Standard Treatment ChiCTR20000 Arm A: Umbilical Cord 60 Unspecified Unspeci Not China 29818 Blood Plasma fied Recruiting (Guangzh (ICTPR) preparations ou reborn Arm B: Standard health Treatment managem ent consultati Journal Pre-proof on co) NCT04293692 Arm A: Umbilical Cord 48 Yes Triple Withdrawn China (ClinicalTrials. MSCs (Wuhan gov) Arm B: Placebo Hamilton Biotechno logy) NCT04273646 Arm A: Umbilical Cord 48 Yes No Not China (ClinicalTrials. MSCs Recruiting (Wuhan gov) Arm B: Placebo Biotechno logy) NCT04269525 Arm A: Umbilical Cord 10 No No Recruiting China (ClinicalTrials. MSCs (Tuohua gov) Biological Technolo gy Co)

Journal Pre-proof

ChiCTR20000 Arm A: Umbilical Cord 60 Yes Double Not China 30138 MSCs Recruiting (ICTPR) Arm B: Placebo ChiCTR20000 Arm A: Umbilical Cord 120 Unspecified Unspeci Not China 30484 MSCs fied Recruiting (ICTPR) Arm B: Umbilical Cord MSCs & derived exosomes Arm C: Placebo ChiCTR20000 Arm A: Umbilical Cord 16 Yes Unspeci Recruiting China 30116 MSCs Dose A fied (ICTPR) Arm B Umbilical Cord MSCs Dose B ChiCTR20000 Arm A: Umbilical Cord 60 Yes No Not China 29816 MSCs Recruiting (Guangzh (ICTPR) Arm B: Standard ou reborn Treatment health managem ent) NCT04313322 Arm A: Wharton Jelly 5 No No Recruiting Jordan (ClinicalTrials. MSCs (Stem gov) Cells Arabia) ChiCTR20000 Arm A: Wharton Jelly 20 Yes Unspeci Not China 30088 MSCs fied Recruiting (ICTPR) Arm B: Saline Plasma Based Therapy ChiCTR20000 Arm A: Convalescent 50 Yes No Recruiting China 30702 Plasma Therapy (ICTPR) Arm B: Standard Treatment ChiCTR20000 Arm A: Anti-2019-nCoV 10 No No Recruiting China 30046 virus inactivated plasma (ICTPR)

ChiCTR20000 Arm A: Anti-SARS-CoV-2 40 Yes No Not China 30381 inactivated Recruiting (ICTPR) convalescentJournal plasma Pre-proof Arm B: Ordinary plasma

ChiCTR20000 Arm A: Anti-SARS-CoV-2 100 Yes Double Not China 30010 virus inactivated plasma Recruiting (ICTPR) Arm B: Ordinary plasma

ChiCTR20000 Arm A: Convalescent 10 No No Recruiting China 30841 Immunoglobulin (ICTPR) Arm B: gamma-globulin NCT04264858 Arm A: Convalescent 10 No No Not China (ClinicalTrials. Immunoglobulin Recruiting gov) Arm B: Gamma globulin ChiCTR20000 Arm A: Convalescent 90 No No Recruiting China 30039 plasma

Journal Pre-proof

(ICTPR) Arm B: Standard Treatment

ChiCTR20000 Arm A: Convalescent 20 No Unspeci Recruiting China 29850 plasma fied (ICTPR) Arm B: Standard Treatment ChiCTR20000 Arm A: Convalescent 30 Yes Unspeci Recruiting China 30627 plasma therapy fied (ICTPR) Arm B: Standard Treatment

ChiCTR20000 Arm A: Convalescent 200 Yes No Recruiting China 29757 plasma therapy (ICTPR) Arm B: Standard Treatment

ChiCTR20000 Arm A: Convalescent 60 Yes Double Not China 30929 Plasma Therapy Recruiting (ICTPR) Arm B: Control Plasma ChiCTR20000 Arm A: Plasma 100 Yes Unspeci Recruiting China 30179 Treatment fied (ICTPR) Arm B: Standard Treatment Inhaled Gas ChiCTR20000 Arm A: Hydrogen 60 Yes No Not China 30258 InhalationC Recruiting (ICTPR) Arm B: Standard Treatment ChiCTR20000 Arm A: Hydrogen- 440 Yes Unspeci Recruiting China 29739 Oxygen Nebulizer fied (ICTPR) Arm B: Oxygen NCT04290871 Arm A: Inhaled Nitric 104 Yes Yes Not yet China (ClinicalTrials. Oxide recruiting gov) Arm B: No intervention NCT04306393 Arm A: Inhaled Nitric 200 Yes Yes Not yet USA (ClinicalTrials. Oxide Journal Pre-proof recruiting gov) Arm B: No intervention NCT04305457 Arm A: Inhaled Nitric 240 Yes No Not yet USA (ClinicalTrials. Oxide recruiting gov) Arm B: No intervention NCT04290858 Arm A: Inhaled Nitric 240 Yes No Not yet China (ClinicalTrials. Oxide recruiting gov) Arm B: No intervention Anti-Fibrotic NCT04282902 Arm A: Pirfenidone 294 Yes No Recruiting China (ClinicalTrials. Arm B: Standard gov) Treatment

Journal Pre-proof

ChiCTR20000 Arm A: Pirfenidone 20 Yes No Recruiting China 30892 Arm B: Standard (ICTPR) Treatment ChiCTR20000 Arm A: Pirfenidone 292 Yes No Recruiting China 30333 Arm B: Standard (ICTPR) Treatment

Anti-Angiogenic NCT04275414 Arm A: Bevacizumab 20 No No Recruiting China (ClinicalTrials. gov) NCT04305106 Arm A: Bevacizumab 118 Yes Triple Recruiting China (ClinicalTrials. Arm B: Standard gov) Treatment NCT04273581 Arm A: Thalidomide 40 Yes Quadru Not China (ClinicalTrials. Arm B: Placebo ple Recruiting gov) NCT04273529 Arm A: Thalidomide 100 Yes Quadru Not China (ClinicalTrials. Arm B: Placebo ple Recruiting gov) Anti-Microbial ChiCTR20000 Arm A: 3% Hydrogen 40 Unspecified Unspeci Not China 30539 Peroxide gargle fied Recruiting (ICTPR) Arm B: Standard Treatment

ChiCTR20000 Arm A: Carrimycin 520 Yes No Recruiting China 29867 Arm B: (ICTPR) Lopinavir/Ritonavir

NCT04286503 Arm A: Carrimycin + 520 Yes No Recruiting China (ClinicalTrials. Basic treatment (Uns.) (Shenyan gov) Arm B: g Tonglian Lopinavir/Ritonavir or Group) Umifenovir or Chloroquine phosphate + Basic treatment (Uns.) ChiCTR20000 Arm A: SuraminJournal 20 Pre-proofNo No Not yet China 30029 recruiting (ICTPR)

Antioxidants ChiCTR20000 Arm A: Alpha Lipoic 68 Yes Unspeci Recruiting China 29851 Acid fied (ICTPR) Arm B: Placebo ChiCTR20000 Arm A: Lipoic Acid 384 Yes Single Recruiting China 30471 Injection (ICTPR) Arm B: Standard Treatment Microbiome ChiCTR20000 Arm A: Newgen beta- 20 Yes Unspeci Recruiting China 30897 gluten probiotic fied (ICTPR)

Journal Pre-proof

Arm B: Standard Treatment ChiCTR20000 Arm A: Probiotics 60 No No Not China 29999 Arm B: Probiotics Recruiting (ICTPR)

ChiCTR20000 Arm A: Probiotics 300 Yes No Recruiting China 29974 Arm B: Standard (Qingdao (ICTPR) Treatment East Sea Pham.) ChiCTR20000 Arm A: Uns. Intestinal 60 Yes Unspeci Recruiting China 29849 Flora Intervention fied (ICTPR) Arm B: Standard Treatment NCT04251767 Arm A: Washed 40 Yes Quadru Enrolling by China (ClinicalTrials. microbiota transplant ple invitation gov) Arm B: Placebo Organ Support ChiCTR20000 Arm A: Artificial Liver 60 No No Recruiting China 30503 System (ICTPR) Arm B: Standard Treatment ChiCTR20000 Arm A: CRRT 152 Unspecified Unspeci Not China 30540 Arm B: CRRT only for fied Recruiting (ICTPR) emergency indication ChiCTR20000 Arm A: CRRT 20 No No Not China 30761 Recruiting (ICTPR) ChiCTR20000 Arm A: ECMO 30 No No Recruiting China 30744 Arm B: Standard (ICTPR) Treatment ChiCTR20000 Arm A: External 200 No No Not China 30855 Diaphragmatic Pacing Recruiting (ICTPR) ChiCTR20000 Arm A: Uns. Blood 20 No No Recruiting China 30773 purification (ICTPR) Therapy Intervention ChiCTR20000 Arm A: EnteralJournal Nutrition 20 Pre-proofYes No Not China 30260 emulsion Recruiting (ICTPR) Arm B: Standard Treatment ChiCTR20000 Arm A: Health 60 Unspecified Unspeci Not China 30198 Education & Pulmonary fied Recruiting (ICTPR) Rehabilitation Arm B: Health Education ChiCTR20000 Arm A: Lung 80 Unspecified Unspeci Recruiting China 30418 Rehabilitation fied (ICTPR) Arm B: Usual Activity ChiCTR20000 Arm A: Lung 40 Unspecified Unspeci Not China 30578 Rehabilitation Training fied Recruiting (ICTPR)

Journal Pre-proof

Arm B: Standard Treatment NCT04283825 Arm A: Psychological 100 No No Not China (ClinicalTrials. and Physical Recruiting gov) Rehabilitation Arm B: Standard Treatment ChiCTR20000 Arm A: Psychological 180 Unspecified Unspeci Recruiting China 30084 Intervention fied (ICTPR) Arm B: Standard Treatment ChiCTR20000 Arm A: Psychological 60 Unspecified Unspeci Not China 30467 intervention & fied Recruiting (ICTPR) Traditional Chinese Medicine Arm B: Psychological Intervention & Traditional Chinese Medicine & Traditional Chinese Medicine Psychological intervention ChiCTR20000 Arm A: Pulmonary 50 Unspecified Unspeci Not China 29459 Rehabilitation fied Recruiting (ICTPR) Arm B: Standard Treatment ChiCTR20000 Arm A: Rehabilitation 80 No No Not China 30433 and Lung Eight-Segment Recruiting (ICTPR) ExerciseD ChiCTR20000 Arm A: Shadowboxing 100 Yes No Not China 29460 Rehabilitation Recruiting (ICTPR) Arm B Standard Treatment Ozonated Auto-hemotherapy ChiCTR20000 Arm A: Conventional 60 No No Recruiting China 30165 treatment (ICTPR) Arm B (mild):Journal Pre-proof Conventional treatment + ozonated autohemotherapy Arm C (severe): Conventional treatment + ozonated autohemotherapy ChiCTR20000 Arm A: Conventional 180 Yes No Recruiting China 30102 treatment (ICTPR) Arm B: Conventional treatment + ozone therapy Arm C (severe): Conventional treatment

Journal Pre-proof

+ ozone therapy Arm D (severe): Conventional treatment Arm E (critical): Conventional treatment + ozone therapy Arm F (critical): Conventional treatment ChiCTR20000 Arm A: Ozonated 60 Yes No Recruiting China 30006 autohemotherapy (ICTPR) Arm B: Standard medical treatment Other ChiCTR20000 Arm A: (General): 90 Yes No Recruiting China 29742 Normal treatment (ICTPR) Arm B (General): Normal treatment + Sodium Aescinate Arm C (Severe): Normal treatment + hormonotherapy (presumed glucocorticoids) Arm D (Severe): Lopinavir/Ritonavir Arm E (Severe): Normal treatment + Sodium Aescinate ChiCTR20000 Arm A: Acetylcysteine 60 Yes Unspeci Not China 30328 inhalation (mucolytic fied Recruiting (ICTPR) effect) via tracheal tube Arm B: Saline inhalation via tracheal tube

ChiCTR20000 Arm A: Bismuth 340 Yes Double Not China 30398 Arm B: Placebo Recruiting (ICTPR) ChiCTR20000 Arm A: ConventionalJournal 460 Pre-proofYes No Recruiting China 30055 treatment (ICTPR) Arm B: Conventional treatment + dipyridamole ChiCTR20000 Arm A: 200 No No Not China 30853 Dexmedetomidine Recruiting (ICTPR) ChiCTR20000 Arm A: Enoxaparin 60 Yes No Not China 30700 Sodium Recruiting (ICTPR) Arm B: Standard Treatment ChiCTR20000 Arm A: High dose 39 Yes Unspeci Not China 30135 Vitamin C fied Recruiting (ICTPR) Arm B: Standard

Journal Pre-proof

Treatment NCT04311697 Arm A: Intravenous 20 Yes Single Not USA & (ClinicalTrials. Aviptadil followed by Recruiting Israel gov) nebulised in 48 hrs if (NeuroRx) required Arm B: Aviptadil nebuliser followed by intravenous in 48hrs if required

ChiCTR20000 Arm A: JakotinibE 8 Unspecified Unspeci Recruiting China 30170 fied (ICTPR) NCT04312009 Arm A: Losartan 200 Yes Quadru Not USA (ClinicalTrials. Arm B: Placebo ple Recruiting gov) NCT04311177 Arm A: Losartan 478 Yes Quadru Not USA (ClinicalTrials. Arm B: Placebo ple Recruiting gov) ChiCTR20000 Arm A: Low molecular 120 Yes Uns. Recruiting China 30946 weight heparin (ICTPR) Arm B: Mechanical Prevention NCT04304313 Arm A: Sildenafil 10 No No Recruiting China (ClinicalTrials. gov) NCT04308317 Arm A: Tetrandrine 60 Yes No Enrolling by China (ClinicalTrials. Arm B: Standard invitation gov) Treatment NCT04264533 Arm A: Vitamin C 140 Yes Triple Recruiting China (ClinicalTrials. Arm B: Sterile Water for gov) Injection

Journal Pre-proof

Journal Pre-proof

Table 1B: Ongoing Clinical Trials for prevention of COVID-19

Clinical Intervention to Prevent Size A Randomised Blinded Status Country Trial ID Infection of Origin (Registry) (Pharma Sponsor)

Vaccine NCT04299724 Arm A: Covid-19/aAPC 100 No No Recruiting China (ClinicalTrials. vaccine gov) NCT04313127 Arm A: Low dose Ad5- 108 No No Not China (ClinicalTrials. nCoV Recruiting (CanSino gov) Arm B: Middle dose Biologics) Ad5-nCoV Arm C: High dose Ad5- nCoV NCT04283461 Arm A: mRNA-1273 45 No No Recruiting USA (ClinicalTrials. (25mcg) (Moderna gov) Arm B: mRNA-1273 TX) (100mcg) Arm C: mRNA-1273 (250mcg)

Antiviral NCT04304053 Arm A: 3040 Yes No Recruiting Spain (ClinicalTrials. Darunavir/Cobicistat gov) Arm B: Isolation ChiCTR20000 Arm A: Interferon a1b 450 Uns. Uns. Not China 30013 Arm B: No intervention Recruiting (ICTPR)

ChiCTR20000 Arm A: Umifenovir 1000 Uns. No Not China 29592 Arm B: Without Recruiting (ICTPR) Umifenovir Antimalarial NCT04303507 Arm A: ChloroquineJournal 10000 Pre-proof Yes Double Not UK (ClinicalTrials. Arm B: Placebo Recruiting gov) NCT04308668 Arm A: 1500 Yes Quadru Recruiting USA (ClinicalTrials. Hydroxychloroquine ple gov) Arm B: Placebo ChiCTR20000 Arm A: 320 Yes No Not China 29803 Hydroxychloroquine – Recruiting (ICTPR) low dose Arm B: Hydroxychloroquine – high dose Arm C: Umifenovir – low dose Arm D: Umifenovir –

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high dose Personal Protective Equipment ChiCTR20000 Arm A: Gastroscope 300 Yes No Not China 30317 mask Recruiting (ICTPR) Arm B: Without mask NCT04296643 Arm A: Medical Masks 676 Yes Single Not USA (ClinicalTrials. Arm B: N95 respirators Recruiting gov) Other NCT04312243 Arm A: Nitric Oxide 460 No No Not USA (ClinicalTrials. Arm B: No treatment Recruiting gov) NCT04313023 Arm A: PUL-042 200 Yes Quadru Not Yet USA (ClinicalTrials. Arm B: Normal Saline ple Recruiting (Pulmotec gov) t) ChiCTR20000 Arm A: Rehabilitation 80 Yes No Not China 30432 and Lung eight-segment Recruiting (ICTPR) exercises Arm B: Normal activity

A Participant size as stated in registry entry B No literature outside trial protocol, likely Tocilizumab C Hydrogen inhalation has shown evidence of antioxidant and anti-inflammatory effects in ischaemia-reperfusion injury D No literature outside trial protocol, likely form of lung rehabilitation E No literature outside trial protocol, possible JAK inhibitor

Abbreviations used: Ad5- adenovirus type 5, APC- antigen presenting cells, CIK cells- Cytokine-induced killer cells, CRRT- Continuous Renal Replacement Therapy, DC – Dendritic Cell, ECMO – Extracorporeal Membrane Oxygenation, IVIG- Intravenous Immunoglobulin, MSCs- Mesenchymal Stem Cells, NK cells – Natural Killer cells, rhG-CSF- recombinant human granulocyte colony-stimulating factor, rSFIN-co- recombinant super-compound interferon, TFF2- Trefoil Factor 2, vMIPJournal- Viral Pre-proof inflammatory protein

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FIGURE LEGENDS Figure 1: Flow diagram showing the study selection process of clinical trials discussed in this article and listed in Table 1. A Data in this registry is incorporated from various national registry’s including Australian & New Zealand, Chinese, Netherlands, Brazil, India, Cuba, Republic of Korea, German, Iranian, Japan, Sri Lanka, Thailand, Peru and also ClinicalTrials.gov, EU Clinical Trials registry, ISRCTNxiand the Pan-Africa. Three studies included treatment for infected patients and an intervention to prevention infection in the uninfected. Figure 2: First recording (week commencing) of clinical trials for COVID-19 in RegistryA by Country (Primary Sponsor/Principal Investigator origin) A Australian & New Zealand, Chinese, Netherlands, Brazil, Indian, Cuba, Republic of Korea, German, Iranian, Japan, Sri Lanka, Thailand, Peru and also ClinicalTrials.gov, EU Clinical Trials registry, ISRCTN and the Pan-Africa registries.

GLOSSARY Adalimumab - Monoclonal antibody targeted against TNF-, an immunosuppressant commonly used in inflammatory conditions Anti-PD-1 antibody - Antibody against Programmed Cell Death Protein 1 (PD-1), inhibition of PD-1 can reverse immune exhaustion, used in oncology treatment (e.g. melanoma) ASC09 - HIV Protease Inhibitor, under development by Ascletis Pharmaceuticals Aviptadil - Vasodilator; short acting alpha-adrenoreceptor antagonist Azvudine – Nucleoside reverse transcriptase inhibitor with efficacy against HCV and HIV Baloxavir Marboxil – Polymerase acidic endonuclease inhibitor approved for influenza Bevacizumab – Monoclonal antibody targeting vascular endothelial growth factor (VEGF) Bismuth – Oral used in treatment of Helicobacter pylori, some evidence of inhibition of SARS coronavirus helicase ATPase Blinding – Experimental Journalprocedure in which thePre-proof participant, investigator, care provider or outcome assessor in a clinical trial are unaware of which treatment arm the participant is receiving. Studies can be described as the number of roles which are blinded i.e. single, double or quadruple blinded study. Blinding reduces the risk of bias in a trials outcome. Carrimycin – Macrolide antibiotic Cytokine-induced killer cells (CIK cell) – CD8+ T cells expanded from ex-vivo stimulation of lymphocytes, used in experimental immunotherapy Cobicistat – CYP3A inhibitor licensed for use in HIV, potentiates action of other antiviral medication

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CytoSorb – Device used in conjunction with dialysis, heamofiltration or extracorporeal membrane oxygenation Danoprevir – NS3/4A protease inhibitor used in treatment of HCV infection Darunavir - HIV protease inhibitor Dexmedetomidine – Sedative 2-adrenergic receptor agonist Dihydroartemisinin/piperaquine - Combination anti-malarial medication Dipyridamole - Antiplatelet medication with is a phosphodiesterase inhibitor, antiviral effects via inhibition of nucleoside uptake Double blind - Where two groups within a study, typically the participant and the outcome assessor, are blinded to the treatment received by the participant

Ebastine - H1 receptor antagonist Eculizumab - Monoclonal antibody which inhibits activation of complement protein C5, used in thrombotic microangiopathy. Emtricitabine/Tenofovir - Combination nucleoside reverse transcriptase inhibitor used in the treatment of HIV-1 Enoxaparin – Low molecular weight heparin, anticoagulant Favipiravir - RNA-dependent RNA polymerase inhibitor, use investigated in RNA viruses such as Influenza, Ebola and viruses GD31 - Described within trial report as novel nucleoside analogue Interferon alpha - Cytokine used in treatment of chronic viral infections such as HBV and HCV Interferon beta 1 b - Cytokine used in the treatment of Multiple Sclerosis Leflunomide - ImmunosuppressiveJournal used in treatmentPre-proof of Rheumatoid Arthritis. Lipoic Acid – Antioxidant Losartan – Angiotensin-II receptor antagonist Novaferon - Recombinant interferon like protein, in vitro and in vivo model evidence of more potent activity than interferon. Open-label – A study in which the treatment received by the participant is known to the participant and investigators. Oseltamivir - inhibitor, licenced for influenza A and B treatment Pegasys - Pegylated interferon alfa-2a. Polyinosinic-Polycytidylic acid - Immunostimulant; Toll like receptor 3 agonist.

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PUL-042 - Immunostimulant; Toll like receptor 2/6/9 agonist. Randomised study – A trial in which the treatment or intervention is randomly allocated to a participant. Randomisation reduces the risk of bias in a trial outcome. Recombinant IL-2 - Cytokine used in cancer immunotherapy treatment (e.g. melanoma). Ribavirin – Guanosine analogue, antiviral agent used in a range of morbific viral infections (e.g HCV, human respiratory syncytial virus & Lassa virus). Ruxolitinib - Selective inhibitor of janus kinase type 1 and 2, used within haematology in polycythaemia vera and myelofibrosis. Sildenafil - Phosphodiesterase type 5 inhibitor, vasodilator used commonly for erectile dysfunction and pulmonary arterial hypertension. Single arm trial – Only one treatment or intervention is being assessed. Sodium Aescinate - Saponin extract of aesculus hippocastanum seeds, investigated for use in lung injury. Sofosbuvir/Daclatasvir – Combination mediation used in treatment of HCV. Sofosbuvir is a nucleotide prodrug and acts as an inhibitor of HCV NS5B RNA-dependant RNA polymerase. Daclatasvir is an HCV NS5A inhibitor. Sofosbuvir/ledipasvir – Combination mediation used in treatment of HCV. Ledipasvir is an inhibitor of HCV NS5A protein. Stem Cell Educator Therapy - Circulation of patient blood through a cell separator followed by brief co-culture of immune cells with cord-blood stem cells and return of the educated immune cells to the patient’s circulation. Suramin - Antitrypanosomal drug used in treatment of African trypanosomiasis. Tetrandrine – BisbenzylisoquinolineJournal alkaloid, Pre-proof calcium channel blocker with anti- inflammatory and immunosuppressant properties. Thalidomide – Anti-angiogenic and immunomodulator used in a range of haematological malignancies including multiple myeloma. Teratogenic anti-emetic causing range of birth defects such as phocomelia. Thymosin - Thymus hormones that stimulated development of T-cells. Tranilast - Antiallergic analogue of a tryptophan metabolite, NLRP3 inflammasome inhibitor Triazavirin - Guanine nucleotide analogue with broad spectrum antiviral effects. Umifenovir (Arbidol) – Non-nucleoside anti-viral membrane fusion inhibitor, licensed in Russia for the treatment of influenza.

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Figure 1

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Figure 2

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