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OE Original

Emerging Treatments in Fight Against COVID-19

Authored By: OrthoEvidence

April 20, 2020


Take home message


More than 120 different interventions, including single and combination treatments, are being or will be investigated in clinical trials for the treatment of COVID-19. The most common classes of medication include antimalarials (e.g., hydroxychloroquine/chloroquine), antivirals (e.g., lopinavir + ritonavir, remdesivir), and some biologics (e.g., monoclonal antibodies, stem cells, convalescent plasma). To date, no treatment has proven to be efficacious via high-quality evidence from randomized clinical trials (RCTs).


With cases of COVID-19 climbing sharply and spreading from one continent to another, the global death toll has surpassed 100,000 people. Thus, effective therapies for COVID-19 are desperately needed. Since we cannot afford to spend years developing and testing new compounds from scratch, many researchers are now repurposing drugs that are already on the market for other diseases and have acceptable safety profiles. 


Hundreds of clinical trials have been initiated by researchers worldwide hoping that, with high-quality evidence, we can quickly discover efficacious interventions for the management of patients with COVID-19 and save thousands of lives. In this OE Original, we summarize what treatments are currently being investigated in clinical trials and highlight the most popular candidates.


Treatment Candidates Against COVID-19


We searched the clinicaltrials.gov website and identified 193 interventional studies whose primary aim is treating COVID-19 (search conducted on April 10, 2020), most of which are RCTs.


More than 120 different treatments, including single and combination treatments, are under investigation (Figure 1). The size of the areas in the sunburst chart correspond to the number of trials in which the treatment is being tested. Popular treatments included: 


  • Hydroxychloroquine or chloroquine alone or plus azithromycin (42 studies)
  • Lopinavir plus ritonavir (12 studies)
  • Stem cells (12 studies)
  • Remdesivir (9 studies)
  • Tocilizumab (10 studies)
  • Convalescent plasma (8 studies)



We also classified the treatment candidates by the severity of COVID-19 (mild, moderate, severe) being studied (Figures 2a-2d). Note that the sum of the number of trials in each category is greater than the overall trial number because some trials are investigating more than one level of severity. We can see that most trials (193) are not studying a treatment for a particular severity level or did not specify the severity of COVID-19. The remaining investigations focused on severe or critically ill patients (38), mild patients (13), and then moderate patients (12). Moreover, when classified by disease severity, the popularity of treatments under investigation basically remains the same. An exception is that stem cell therapies are more prevalent when considering research on patients with severe or critical COVID-19.






A Glance at Some of the Most Popular Candidate Treatments Against COVID-19


  • Hydroxychloroquine/Chloroquine alone or plus azithromycin (42 studies)


Chloroquine and hydroxychloroquine are generally used for treating malaria and certain inflammatory conditions such as rheumatoid arthritis, while azithromycin is an antibiotic for the treatment of bacterial infections such as respiratory infection. They have shown some antiviral activity against novel coronavirus in vitro (Wang et al., 2020; Yao et al., 2020). However, there is still a lack of RCT evidence. A non-peer-reviewed study published on MedRxiv showed that hydroxychloroquine could significantly shorten the time to clinical recovery and advance the resolution of pneumonia (Chen et al., 2020). An open-label non-RCT published in a peer-reviewed journal also suggested that hydroxychloroquine plus azithromycin significantly reduces viral load (Gautret et al., 2020).


Recommendations for using hydroxychloroquine/chloroquine are controversial across agencies. For example, the National Health Commission of the People's Republic of China (2020) recommends the use of hydroxychloroquine/chloroquine without providing any RCT evidence. The interim guidance from the American Thoracic Society suggests hydroxychloroquine/chloroquine only for patients who are hospitalized and whose clinical condition is severe enough to warrant investigational therapy (Wilson et al., 2020). The British Columbia Centre for Disease Control of Canada (2020) recommends against the use of hydroxychloroquine/chloroquine outside of clinical trials. The United States Food and Drug Administration (FDA) has issued an emergency use authorization (EUA) for the emergency use of oral chloroquine and hydroxychloroquine for the treatment of COVID-19 among hospitalized patients (The United States Food and Drug Administration (FDA), 2020a).


  • Lopinavir + Ritonavir (12 studies)


Lopinavir + ritonavir is a combination of antiviral agents used in the treatment of human immunodeficiency virus (HIV). Lopinavir can effectively inhibit the protease activity of past coronavirus in vitro, such as MERS-CoV (Chan et al., 2015). However, to our knowledge, there are no in vitro studies on novel coronavirus reported so far. Ritonavir can increase the half-life of lopinavir. Evidence from RCTs is limited. An RCT on 200 patients by Cao et al. (2020) found no benefits with lopinavir + ritonavir in hospitalized adult patients with severe COVID-19, compared to standard care. 


The World Health Organization (WHO) has not indicated its position on the use of lopinavir + ritonavir for the treatment of COVID-19. The British Columbia Centre for Disease Control of Canada (2020) recommends against the routine use of lopinavir + ritonavir outside of clinical trials. However, another interim guidance suggests clinicians consider the use of lopinavir + ritonavir when hospitalized patients with < 12 days of symptomatic illness do not require mechanical ventilation (Alberta Health Services, 2020).


  • Remdesivir (9 studies)


Remdesivir is not an FDA-approved treatment agent and, thus, not commercially available. Remdesivir inhibits RNA-dependent RNA polymerase and has demonstrated antiviral activity in vitro and in animal models against the MERS-CoV and SARS-Cov (Sheahan et al., 2020).


A study published on April 10, 2020, in the New England Journal of Medicine, showed that 36 out of 53 COVID-19 patients (68%) who received at least one dose of remdesivir showed improvement in their conditions. Although the results are very promising, the study has serious drawbacks. For instance, it lacks a control arm which makes it impossible to determine how much, if any of the improvement was due to remdesivir (Grein et al., 2020).


To date, the WHO has not taken a position on the use of remdesivir to treat COVID-19. It does include remdesivir as one arm in its ongoing global collaborative SOLIDARITY trial. 


  • Tocilizumab (10 studies)


Tocilizumab is an anti-interleukin 6 monoclonal antibody used for treatment of rheumatoid arthritis. Currently, we only have some case reports showing improvement in patients with severe COVID-19 after receiving tocilizumab (De Luna et al., 2020; Michot et al., 2020).


The WHO and US Center for Disease Control (CDC) have not revealed their position on the use of tocilizumab in COVID-19. The interim guidance from the American Thoracic Society (2020) makes no recommendation for or against using tocilizumab for hospitalized COVID-19 patients with pneumonia. However, the British Columbia Centre for Disease Control of Canada (2020) and the Alberta Health Services (2020) explicitly recommend against the routine use of tocilizumab.


  • Mesenchymal Stem Cells (MSCs, 12 studies)


MSCs have been widely used in cell-based therapy. Not only do they possess differentiation abilities but they are also effective immunomodulators. The immunomodulatory effects of MSCs are triggered by the activation of toll-like receptors in MSCs, which are stimulated by double-stranded RNA from a virus (Li et al., 2012). A recent non-RCT showed that the pulmonary function and symptoms of 7 patients with COVID-19 were significantly improved after MSC transplantation, compared with 3 patients in the placebo control group. However, the results were inconclusive. 


Recently, the US Food and Drug Administration (FDA) approved several clinical trials aiming to use MSC treatments in COVID-19 patients. To our knowledge, there are no recommendations existing on whether MSCs should be used to target COVID-19.


  • Convalescent Plasma (8 studies)


Convalescent plasma therapy, a type of immunotherapy, has been applied to the treatment of many infectious diseases. A meta-analysis, which was published in 2015 and included 32 studies investigating SARS and severe influenza, showed a significant reduction in mortality following convalescent plasma therapy compared with the placebo or no therapy group (odds ratio (OR), 0.25; 95% confidence interval (CI), 0.14 to 0.45) (Mair-Jenkins et al., 2015).


Currently, we don’t have any evidence from RCTs available to support the use of convalescent plasma in patients with COVID-19. There are, however, some results generated from non-randomized interventional studies. For example, a study showed that a single 200 ml transfusion of convalescent plasma significantly improved the clinical symptoms of 10 adult patients with COVID-19 compared to their status before transfusion (Duan et al., 2020).


The US FDA has approved the use of convalescent plasma to treat patients who have severe or immediately life-threatening COVID-19, provided that doctors get approval before its use (The United States Food and Drug Administration (FDA), 2020b). 


Besides those mentioned above, there are some candidate treatments which are less popular in terms of the number of registered trials, but news cycles have been paying attention to them more recently. For example, baricitinib (also called Olumiant, a JAK1 and JAK2 inhibitor for the treatment of rheumatoid arthritis in adults) had only 3 trials registered on Clinicaltrials.gov by April 10th, 2020; however, the New York Times has been reporting on this treatment in recent articles. Currently, we could not find any formal recommendation from major agencies about the use of baricitinib against COVID-19.



Attitudes and Expectations in the Medical Community


The attitudes towards the hundreds of clinical trials that have been initiated and expectations of the various candidate treatments against COVID-19 are controversial. A newly published report in the Lancet addressed this issue (Mullard, 2020).

In this report, some experts revealed their concerns about the fact that people have rushed into clinical trials and all these trials lack comprehensive trial coordination mechanisms:

            “The scale of these trials is too small, and the variation in terms of how they are being run is too large. These trials aren't really designed to answer the questions that need to be answered.”  

-- John-Arne Røttingen, chief executive of the Research Council of Norway and proponent of a more collaborative approach --

Some other experts partially agree with the above statement, but also see the other side of the argument:

            “On the one hand, we want to be coordinated. On the other hand, we don't want to spend too much time getting coordinated because the pace of this thing is so rapid. Everyone's doing their best.”

-- Merdad Parsey, chief medical officer at Gilead --

As for the expectations of the numerous candidate treatments, experts are also mixed.

            “Will we have a magic bullet? Most likely not.”

-- Marie-Paule Kieny, director of research at The Institut national de la santé et de la recherche médicale --

“I don't want to set expectations too high. I'm not saying these will be a cure for COVID-19. But even if we can reduce the proportion of patients that need ventilators by, say, 20%, that could have a huge impact on our national health-care systems.”

-- John-Arne Røttingen --


Summary


While nearly 200 trials are being conducted regarding a variety of potential treatments, the current evidence lacks any support for a particular treatment. Despite this, there have been several national agencies that have recommended the use of some interventions, usually in more severe cases where experimental treatment or compassionate use is warranted.



References


Alberta Health Services. (2020). Recommendations for Antimicrobial Management of Adult Hospitalized Patients with COVID-19. Retrieved from https://www.albertahealthservices.ca/assets/info/ppih/if-ppih-covid-19-recommendations.pdf 

Date accessed: April 12, 2020


The British Columbia Centre for Disease Control. (2020). Unproven Therapies for COVID-19. Retrieved from http://www.bccdc.ca/Health-Professionals-Site/Documents/Guidelines_Unproven_Therapies_COVID-19.pdf Date accessed: April 12, 2020


Cao, B., Wang, Y., Wen, D., Liu, W., Wang, J., Fan, G., . . . Wang, C. (2020). A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. doi:10.1056/NEJMoa2001282


Chan, J. F., Yao, Y., Yeung, M. L., Deng, W., Bao, L., Jia, L., . . . Yuen, K. Y. (2015). Treatment With Lopinavir/Ritonavir or Interferon-beta1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. J Infect Dis, 212(12), 1904-1913. doi:10.1093/infdis/jiv392


Chen, Z., Hu, J., Zhang, Z., Jiang, S., Han, S., Yan, D., . . . Zhang, Z. (2020). Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv, 2020.2003.2022.20040758. doi:10.1101/2020.03.22.20040758


Duan, K., Liu, B., Li, C., Zhang, H., Yu, T., Qu, J., . . . Yang, X. (2020). Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci USA. doi:10.1073/pnas.2004168117


De Luna, G., Habibi, A., Deux, J. F., Colard, M., d'Alexandry d'Orengiani, A., Schlemmer, F., . . . Bartolucci, P. (2020). Rapid and Severe Covid-19 Pneumonia with Severe Acute Chest Syndrome in a Sickle Cell Patient Successfully Treated with Tocilizumab. Am J Hematol. doi:10.1002/ajh.25833


Mullard, A. (2020). Flooded by the torrent: the COVID-19 drug pipeline. The Lancet, Retrieved from https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)30894-1.pdf Date accessed: April 17, 2020


The United States Food and Drug Administration (FDA). (2020a). Emergency Use Authorization (EUA) to authorize use of chloroquine and hydroxychloroquine. Retrieved from https://www.fda.gov/media/136534/download Date accessed: April 12, 2020


The United States Food and Drug Administration (FDA). (2020b). Recommendations for Investigational COVID-19 Convalescent Plasma. Retrieved from  https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma Date accessed: April 12, 2020


Gautret, P., Lagier, J. C., Parola, P., Hoang, V. T., Meddeb, L., Mailhe, M., . . . Raoult, D. (2020). Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents, 105949. doi:10.1016/j.ijantimicag.2020.105949


Grein, J., Ohmagari, N., Shin, D., Diaz, G., Asperges, E., Castagna, A., . . . Flanigan, T. (2020). Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. doi:10.1056/NEJMoa2007016


Li, W., Ren, G., Huang, Y., Su, J., Han, Y., Li, J., . . . Shi, Y. (2012). Mesenchymal stem cells: a double-edged sword in regulating immune responses. Cell Death Differ, 19(9), 1505-1513. doi:10.1038/cdd.2012.26


Mair-Jenkins, J., Saavedra-Campos, M., Baillie, J. K., Cleary, P., Khaw, F. M., Lim, W. S., . . . Convalescent Plasma Study, G. (2015). The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis, 211(1), 80-90. doi:10.1093/infdis/jiu396


Michot, J. M., Albiges, L., Chaput, N., Saada, V., Pommeret, F., Griscelli, F., . . . Stoclin, A. (2020). Tocilizumab, an anti-IL6 receptor antibody, to treat Covid-19-related respiratory failure: a case report. Ann Oncol. doi:10.1016/j.annonc.2020.03.300


National Health Commission of the People's Republic of China. (2020). Interpretation of COVID-19 treatment guidelines (6th version). http://www.gov.cn/zhengce/2020-02/19/content_5480958.htm 

Date accessed: April 12, 2020


Sheahan, T. P., Sims, A. C., Leist, S. R., Schafer, A., Won, J., Brown, A. J., . . . Baric, R. S. (2020). Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun, 11(1), 222. doi:10.1038/s41467-019-13940-6


Wang, M., Cao, R., Zhang, L., Yang, X., Liu, J., Xu, M., . . . Xiao, G. (2020). Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res, 30(3), 269-271. doi:10.1038/s41422-020-0282-0 


Wilson KC, Chotirmall SH, Bai C, Rello J.  COVID-19: Interim Guidance on Management  Pending Empirical Evidence. (2020). https://www.thoracic.org/professionals/clinical-resources/disease-related-resources/covid-19-guidance.pdf Date accessed: April 12, 2020


Yao, X., Ye, F., Zhang, M., … Liu, D. (2020). In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Clinical Infectious Diseases, ciaa237, https://doi.org/10.1093/cid/ciaa237

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