key: cord-343090-dsjq98ks
authors: Fragkou, Paraskevi C.; Belhadi, Drifa; Peiffer-Smadja, Nathan; Moschopoulos, Charalampos D.; Lescure, François-Xavier; Janocha, Hannah; Karofylakis, Emmanouil; Yazdanpanah, Yazdan; Mentré, France; Skevaki, Chrysanthi; Laouénan, Cédric; Tsiodras, Sotirios
title: Review of trials currently testing treatment and prevention of COVID-19
date: 2020-05-23
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2020.05.019
sha: 
doc_id: 343090
cord_uid: dsjq98ks

BACKGROUND: As COVID-19 cases continue to rise globally, evidence from large randomised controlled trials is still lacking. Currently, numerous trials testing potential treatment and preventative options are undertaken all over the world. OBJECTIVES: We summarised all registered clinical trials examining treatment and prevention options for COVID-19. Additionally, we evaluated the quality of the retrieved studies. DATA SOURCES: Clinicaltrials.gov, the Chinese Clinical Trial Registry and the European Union Clinical Trials Register were systematically searched. STUDY ELIGIBILITY CRITERIA: Registered clinical trials examining treatment and/or prevention options for COVID-19 were included. No language, country or study design restrictions were applied. We excluded withdrawn or cancelled studies and trials not reporting therapeutic or preventative strategies for COVID-19. PARTICIPANTS: and interventions: No restrictions in terms of participants’ age and medical background or type of intervention were enforced. METHODS: The registries were searched using the term “coronavirus” or “COVID-19” from their inception until 26(th) March 2020.Additional manual search of the registries was also performed. Eligible studies were summarised and tabulated. Interventional trials were methodologically analysed, excluding expanded access studies and trials testing Traditional Chinese Medicine. RESULTS: In total, 309 trials evaluating therapeutic management options, 23 studies assessing preventive strategies and 3 studies examining both were retrieved. Finally, 214 studies were methodologically reviewed. Interventional treatment studies were mostly randomised (n=150, 76%) and open-label (n=73, 37%) with a median number of planned inclusions of 90 (IQR 40-200). Major categories of interventions that are currently being investigated are discussed. CONCLUSION: Numerous clinical trials have been registered since the onset of the COVID-19 pandemic. Summarised data on these trials will assist physicians and researchers to promote patient care and guide future research efforts for COVID-19 pandemic containment.

Given the steep upsurge of COVID-19 cases worldwide within an unprecedented short period 60 9 Azvudine, an azidocytidine analogue that inhibits viral reverse transcriptase, has been 153 effective against HIV, hepatitis B and C viruses [29] . Its efficacy against SARS-CoV-2 is 154 being tested in 3 ongoing clinical trials (Table 1, Table S1 ). Another nucleoside analogue 155 undergoing investigation for COVID-19 pneumonia is emtricitabine/tenofovir alafenamide. 156 157

Chloroquine and hydroxychloroquine are currently licensed for the treatment of malaria and 159 autoimmune diseases [30] . However, they have also been studied against several viruses with 160 promising in vitro results, never confirmed in humans [31] [32] [33] . As weak bases, they are 161 concentrated in acidic intra-cellular organelles, leading to alkalization and disruption of the 162 low pH-dependent steps of viral replication, including viral-cell fusion and uncoating [30, 32] . 163 Moreover, they impair the terminal glycosylation of ACE2 receptor in Golgi apparatus, thus 164

inhibiting the viral penetration into the host cells [34] . 165

As they are accumulated in lymphocytes and macrophages, these drugs reduce secretion of 166 proinflammatory cytokines, and particularly of tumour necrosis factor alpha (TNF-α) [33] . 167

Experimental data demonstrated that chloroquine is highly effective in vitro against SARS-168

CoV-2 in an estimated effective concentration that is easily achievable with standard dosing 169 regimens [25] . However, the efficacy of anti-malaria drugs in clinical practice is still much 170 debated. Some preliminary reports from ongoing trials supporting their effectiveness, alone or 171 in combination with azithromycin [35, 36] , have been called into question on the basis of their 172 methodology. Moreover, these results were challenged by new trials that did not find 173 any substantial benefit from hydroxychloroquine administration [37] [38] [39] . . Therefore, clinical 174 trials with a control group are needed to provide reliable answers for clinicians; antimalaria 175 drugs are being tested in 30 randomised controlled trials (Table 1, Table S1 ).

Virus-induced immune response leading to cytokine storm syndrome (CSS) and secondary 179 haemophagocytic lymphohistiocytosis (HLH) is probably the underlying pathogenetic 180 mechanism that leads to critical and often fatal COVID-19 infection [40, 41] . (Table 1, Table S1 ); 189 tocilizumab, in particular, improved symptoms and laboratory parameters in a small Immunomodulators licensed for haematological and rheumatological conditions (such as 197 leflunomide and thalidomide), as well as colchicine that counteracts the assembly of the 198 NLRP3 inflammasome, are also being studied for their therapeutic use against SARS-CoV-2 199 (Table 1,Table S1 ) [44] . The immunomodulatory effects of macrolide antibiotics, as well as their pharmacodynamic 201

property to achieve at least 10-fold higher concentrations in epithelial lung fluid than in 202 serum, have led researchers to repurpose them against SARS-CoV-2 (Table 1, Table S1 observations the antifibrotic agent pirfenidone is being evaluated in at least three randomised 215 clinical trials for its efficacy in the prevention of post-COVID-19 pneumonia fibrosis (Table  216 1, Table S1 ). Pirfenidone targets collagen synthesis by inhibiting transforming growth factor 217 beta (TGF-b), diminishing extracellular matrix deposition and reducing the activity of lung 218 fibroblasts in vitro [53] . 219

Finally, immunostimulatory molecules that enhance the hosts' immune response against the 220 invading pathogen, like IFN-α, interferon beta (IFN-β), the recombinant protein produced by (Table 1, Table S1 ). (Table 1, Table S1 ). (Table 2, Table S2 ). 293

Many studies are currently evaluating the efficacy of TCM in COVID-19 prevention in 294

China. Importantly, at least 4 vaccines are under development. Among them, an mRNA-based 295 vaccine encoding the S-protein is being assessed for its safety, reactogenicity and efficacy 296 against SARS-CoV-2 (Table 2, Table S2 ). Besides the registered trials, other large companies 297

have also announced the initiation of vaccine development [81, 82] . 298

Other preventative molecules include hydroxychloroquine and the recombinant human 299 interferon α1b spray. In the USA, exposed individuals are randomised to hydroxychloroquine 300 or placebo, evaluating the agent's potential as post-exposure prophylaxis (NCT04308668, 301 Table S2 ). Furthermore, another randomised clinical trial evaluates the efficacy of a 3-month 302 course of chloroquine in at-risk healthcare personnel (NCT04303507 , Table S2 ). Finally, the 303 live attenuated strain of Mycobacterium bovis is expected to be tested as a preventative 304 strategy against COVID-19 among healthcare professionals, in Australia and France. 305 306

In total, 198 interventional treatment and 16 prevention trials were included in the 309 methodological analysis respectively (Table 3) . Among the eligible treatment studies, 310 children recruitment (i.e.< 14 years old) was reported in 7 clinical trials in total: 1 testing 311 darunavir with cobicistat (NCT04252274); 2 on human stem cells transfusion 312 (ChiCTR2000029606, ChiCTR2000030944); 1 testing hydroxycholoroquine (EudraCT 313

Number: 2020-000890-25); 1 using tocilizumab (NCT04317092); and 1 assessing nutritional 314 supplements (NCT04323345) ( Table S1 ).With respect to relevant prevention studies, children 315

were included in 2 vaccine trials (NCT04276896, NCT04299724) as shown in Table S2 . 316 317

Phase IV and phase III treatment trials were the most commonly reported interventional study 319 types (n=40, 20% and n=35, 18% respectively) as demonstrated in Table 3 . Nonetheless, the 320 majority of registered trials do not disclose the study phase (n=83, 42%). 321

In terms of blinding, 73 open-label (37%), 31 double-blinded (16%), and 16 single-blinded 322 (8%) studies were retrieved. Most trials were randomised (n=150, 76%) with a parallel 323 assignment between arms. The median (IQR) number of planned inclusions is 90 (40-200) 324 with a range of 5 to 6000 participants. 325

Phase III and phase I prevention studies were the most commonly reported ones (n=6, 38% 326 and n=3, 19% respectively, Table3). As with treatment trials, many prevention trials do not 327 report the study phase (n=4, 25%). 328

Regarding prevention studies' blinding, 6double-blinded (38%), 5open-label (31%), and 2 329 single-blinded (13%) were found. Most studies were randomised (n=10, 63%) with a parallel Figure 5 shows 341 the total number of planned inclusions and the number of clinical trials for the ten most 342 frequently studied treatments, with hydroxychloroquine being the treatment associated with

A clinical primary outcome was defined in 128 out of 198 therapeutic trials (65% ; Table 3) . (6%) studies respectively (Table 3) . 354

Regarding prevention studies,10 out of 16 (62%)disclosed a clinical primary outcome , such 355 as confirmed symptomatic COVID-19 for 3studies, severe COVID-19 for 2 studies, 356 confirmed or suspected COVID-19 for one study, and safety for 4 (studies evaluating 357 vaccines. The other prevention studies had a virological outcome (confirmed SARS-CoV-2 358 infection with or without symptoms, n=5) or a biological outcome (n=1, routine blood tests) 359 (Table 3) . analyse clinical trials testing these agents. 394

Firstly, study design data and details on the interventions being assessed were often lacking. 397

This hampers the available information to researchers and relevant stakeholders, and 398 potentially influences the discovery of successful treatments. 399

Secondly, most trials, and especially those registered at the beginning of the pandemic, 400 disclosed low participant numbers, which may impact the robustness of their future results. 401

However, these numbers should be cautiously interpreted, as they represent the anticipated, 

The progression of computed tomographic (CT) 592 images in patients with coronavirus disease (COVID-19) pneumonia

The CT progression of COVID-19 pneumonia

Integrating mechanisms of pulmonary fibrosis

Induction of pro-598 inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19

COVI-19 or SARS-CoV-2): anti-inflammatory strategies

Pirfenidone attenuates 602 lung fibrotic fibroblast responses to transforming growth factor-β1

DisCoVeRy French Steering Committee. Type 1 interferons as a potential treatment 606 against COVID-19

Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers in

TMPRSS2 and ADAM17 Cleave ACE2 Differentially and Only Proteolysis by 617 TMPRSS2 Augments Entry Driven by the Severe Acute Respiratory Syndrome

Renin-Angiotensin System Blockers and the

COVID-19 Pandemic: At Present There Is No Evidence to Abandon Renin

Camostat Mesilate, Pancrelipase, and Rabeprazole Combination Therapy Improves 627

Epigastric Pain in Early Chronic Pancreatitis and Functional Dyspepsia with

Arbidol as a broad-spectrum antiviral: an update

Antiviral activity of arbidol 639 against influenza A virus, respiratory syncytial virus, rhinovirus, coxsackie virus and 640 adenovirus in vitro and in vivo

Pharmacokinetics, metabolism, 643 and excretion of the antiviral drug arbidol in humans

Arbidol combined with LPV/r 648 versus LPV/r alone against Corona Virus Disease 2019:a retrospective cohort study

Evaluation of convalescent whole blood for treating Ebola Virus Disease in Freetown

Treatment of severe acute respiratory 654 syndrome with convalescent plasma

Use of 656 convalescent plasma therapy in SARS patients in Hong Kong

Retrospective 659 comparison of convalescent plasma with continuing high-dose methylprednisolone 660 treatment in SARS patients

The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the 664 treatment of severe acute respiratory infections of viral etiology: a systematic review 665 and exploratory meta-analysis

Feasibility 668 of Using Convalescent Plasma Immunotherapy for MERS-CoV Infection

Disappearance of antibodies to

SARS-associated coronavirus after recovery

Therapeutic 674 Implications of Human Umbilical Cord Mesenchymal Stromal Cells in Attenuating 675

Influenza A(H5N1) Virus-Associated Acute Lung Injury

Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19

Exosomes derived from mesenchymal stem cells

Exosomes from mesenchymal stem/stromal cells: A new 683 therapeutic paradigm

Moderna's COVID-19 vaccine could reach healthcare workers this fall | FierceBiotech 693 n

Johnson identifies lead COVID-19 vaccine candidate n.d

WHO R&D Blueprint novel Coronavirus COVID-19 Therapeutic Trial Synopsis

Drug treatment options for the 2019-new coronavirus (2019-nCoV)

COVID-19 infection: the 703 perspectives on immune responses

Early antiviral treatment contributes 706 to alleviate the severity and improve the prognosis of patients with novel coronavirus 707 disease (COVID-19)

Temporal 709 profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study

Clinical features of patients 713 infected with 2019 novel coronavirus in Wuhan, China

COVID-19: 716 combining antiviral and anti-inflammatory treatments

NIH clinical trial of investigational vaccine for COVID-19 begins | National Institutes 721 of Health (NIH) n.d

Chloroquine/ Hydroxychloroquine Prevention of Coronavirus Disease (COVID-19) in

the Healthcare Setting -Full Text View -ClinicalTrials

Molecular immune pathogenesis and diagnosis 727 of COVID-19

Xpress SARS-CoV-2 has received FDA Emergency Use (COVID-19) globally