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COMMENTARY
Year : 2020  |  Volume : 15  |  Issue : 2  |  Page : 49-51
Clinical trials for coronavirus disease 2019: What is being evaluated and what is not


1 Intensive Care Department, Ministry of National Guard Health Affairs; King Abdullah International Medical Research Center; Intensive Care Department, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
2 Intensive Care Department, Prince Mohammed Bin Abdulaziz Hospital - Ministry of Health, Riyadh, Saudi Arabia
3 Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
4 Interdepartmental Division of Critical Care Medicine, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Toronto, Canada
5 College of Medicine, King Saud Bin Abdulaziz University for Health Sciences; Department of Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia

Date of Submission12-Mar-2020
Date of Acceptance17-Mar-2020
Date of Web Publication20-Mar-2020

Correspondence Address:
Prof. Yaseen M Arabi
Intensive Care Department, Respiratory Services, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, P.O. Box 22490 Riyadh 11426
Saudi Arabia
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DOI: 10.4103/atm.ATM_99_20

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   Abstract 


Since the report of the first case of coronavirus disease 2019 (COVID-19) in China in late December 2019, there have been 204 610 cases worldwide as of 18 March, 2020. As part of the response to this outbreak, there has been an impressive amount of research undertaken to better characterize the disease and to evaluate therapeutic options. By March 12, 2020, there are more than 382 studies registered in the clinical trials databases addressing COVID-19 including more than 80 randomized controlled trials.


Keywords: Clinical trials, coronavirus disease 2019, outbreak response


How to cite this article:
Arabi YM, Asseri A, Webb S, Marshall J, Al Moamary MS. Clinical trials for coronavirus disease 2019: What is being evaluated and what is not. Ann Thorac Med 2020;15:49-51

How to cite this URL:
Arabi YM, Asseri A, Webb S, Marshall J, Al Moamary MS. Clinical trials for coronavirus disease 2019: What is being evaluated and what is not. Ann Thorac Med [serial online] 2020 [cited 2020 Aug 12];15:49-51. Available from: http://www.thoracicmedicine.org/text.asp?2020/15/2/49/281112




Since the report of the first cases of coronavirus disease 2019 (COVID-19) in China in late December 2019, there have been 204 610 cases worldwide as of March 18 2020. While cases are declining in China, there has been a sharp increase in the number of cases across more than 120 countries outside China. The reported case fatality rate of COVID-19 is approximately 1%–4%.[1] A study from China classified COVID-19 patients into nonsevere cases constituting 80% and severe cases constituting 20% of patients.[2] In total, 5% of COVID-19 patients were critically ill and were admitted to the intensive care units, with a mortality rate of 49%–62%.[2],[3] This high mortality rate among critically ill COVID-19 patients is reminiscent of what was observed among critically ill patients with Middle East respiratory syndrome (MERS).[4],[5] The disease affects different age groups; with older patients being at the highest risk.[2]

As part of the response to this outbreak, there has been an impressive amount of research undertaken to better characterize the disease and to evaluate therapeutic options. By March 12, 2020, there are more than 382 studies registered in the clinical trial databases addressing COVID-19 including more than 80 randomized controlled trials.[6],[7]

Currently registered clinical trials are evaluating a wide variety of interventions [6,7] [Table 1]. Antiviral agents under study include remdesivir, lopinavir/ritonavir, and other antiretroviral agents, chloroquine, and several anti-influenza antiviral agents. Several interferons including interferons alpha-1b, alpha-2b, beta-1a, and beta-1b are also being examined. A host of biological therapeutics including mesenchymal stem cells, immunoglobulin, and convalescent plasma are being tested as well. Different immunomodulators are also being evaluated.
Table 1: Interventions being evaluated for coronavirus disease 2019 based on registered trials

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What appears to be missing from the list of the ongoing clinical trials are the interventions related to supportive care, which arguably are very important in determining patient outcomes. For example, noninvasive ventilation and high-flow nasal cannula have been widely used in the ongoing COVID-19 outbreak, but data about efficacy and safety are lacking.[3] In critically ill patients with MERS, 35% of patients received noninvasive ventilation; however, this use was associated with high failure rate reaching 92%.[8] Importantly, patients intubated after failed noninvasive ventilation were more likely to require oxygen rescue therapy than those who were intubated without noninvasive ventilation.[8] Although all the studies showed that noninvasive ventilation was not associated with different mortality, these findings raise concern about the efficacy of noninvasive ventilation; therefore, these important therapeutics should be considered as high research priority.[8] The use of extracorporeal membrane oxygenation in the current COVID-19 outbreak has been reported in several centers, but data are needed. Studies on COVID-19 reported high incidence of arrhythmias reaching 41% in one report among critically ill patients with COVID-19.[9] The extent of cardiac involvement is unknown at present; however, myocardium involvement is not uncommon with influenza virus infection and myocarditis in this context is well known.[10] Therefore, more data about the clinical involvement of the myocardium are needed. The implications on the management in terms of fluid therapeutics and type of inotropes required need to be further studied.

What is needed is a research agendum that addresses different questions related to the management of COVID-19. The World Health Organization (WHO) in collaboration with the Global Research Collaboration for Infectious Disease Preparedness has held the Global Research and Innovation Forum on February 11–12, 2020, to identify the urgent priorities for COVID-19 research. The domains that were addressed included the natural history of the virus, transmission and diagnosis, animal and environmental research, epidemiological studies, clinical characterization and management, infection prevention and control, therapeutics and vaccines, ethical considerations for research, and integration of social sciences into the outbreak response.[11] Informal consultation on research prioritization of candidate therapeutic agents by the WHO has prioritized remdesivir for clinical trials followed by lopinavir/ritonavir and interferon beta-1b combination.[12] The WHO Master Protocol for multicenter, adaptive, randomized controlled trial addresses several therapeutics in hospitalized patients with COVID-19.[13] Prioritization of questions related to support care is urgently needed. Several questions may be addressed in adaptive design trials. The randomized, embedded, multifactorial adaptive platform trial for community-acquired pneumonia (REMAP-CAP) is designed as an adaptive preplanned, preapproved platform trial for ICU patients with severe community-acquired pneumonia.[14] The trial evaluates multiple interventions and their interactions.[14] The REMAP-CAP has now been adjusted to include domains related to the COVID-19. This design increases the efficiency of the research process and helps addressing important questions related to COVID-19 on an urgent basis.

Financial support and sponsorship

Nil.

Conflicts of interest

Dr. Arabi is the principal investigator on a clinical trial for lopinavir/ritonavir and interferon in Middle East respiratory syndrome (MERS) and that he was a nonpaid consultant on antivirals for MERS-coronavirus (CoV) for Gilead Sciences and SAB Biotherapeutics. He is a co-investigator on REMAP-CAP. Dr Arabi and Dr Webb are investigators on REMAP-CAP and Board Members of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). Dr. Marshall is the Chair of the International Forum for Acute Care Trialists (InFACT), and co-chair of the WHO working group on clinical characterization; he has no relevant commercial conflicts to disclose.



 
   References Top

1.
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020. DOI: 10.1056/NEJMoa2002032.  Back to cited text no. 1
    
2.
Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. Jama 2020.  Back to cited text no. 2
    
3.
Yang X, Yu Y, Xu J, Shu H, Liu H, Wu Y, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. The Lancet Respiratory Medicine 2020.  Back to cited text no. 3
    
4.
Arabi YM, Murthy S, Webb S. COVID-19: A novel coronavirus and a novel challenge for critical care. Intensive Care Medicine. 2020:1-4. DOI: 10.1007/s00134-020-05955-1.  Back to cited text no. 4
    
5.
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. Jama 2020.  Back to cited text no. 5
    
6.
World Health Organization. International Clinical Trials Registry Platform (ICTRP). Available from: https://www.who.int/ictrp/network/chictr/en/. [Last accessed on 2020 Mar 12].  Back to cited text no. 6
    
7.
World Health Organization. The ICTRP Search Portal. Available from: http://apps.who.int/trialsearch/default.aspx. [Last accessed on 2020 Mar 12].  Back to cited text no. 7
    
8.
Alraddadi BM, Qushmaq I, Al-Hameed FM, Mandourah Y, Almekhlafi GA, Jose J, et al. Noninvasive ventilation in critically ill patients with the Middle East respiratory syndrome. Influenza Other Respir Viruses 2019;13:382-90.  Back to cited text no. 8
    
9.
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020.  Back to cited text no. 9
    
10.
Arabi YM, Fowler R, Hayden FG. Critical care management of adults with community-acquired severe respiratory viral infection. Intensive Care Med 2020;46:315-28.  Back to cited text no. 10
    
11.
World Health Organization. World Experts and Funders Set Priorities for COVID-19 Research. Available from: https://www.who.int/news-room/detail/12-02-2020-world-experts-and-funders-set-priorities-for-covid-19-research. [Last accessed on 2020 Mar 12].  Back to cited text no. 11
    
12.
World Health Organization. Informal Consultation on Prioritization of Candidate Therapeutic Agents for Use in Novel Coronavirus 2019 Infection. World Health Organization; 2020. Available from: https://apps.who.int/iris/bitstream/handle/10665/330680/WHO-HEO-RDBlueprint%28nCoV%29-2020.1-eng.pdf. [Last accessed on 2020 Mar 10].  Back to cited text no. 12
    
13.
World Health Organization. Master Protocol. A Multi-Centre, Adaptive, Randomized, Double-Blind, Placebo Controlled Clinical Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Patients. Available from: https://www.who.int/blueprint/priority-diseases/key-action/multicenter-adaptive-RCT-of-investigational-therapeutics-for-COVID-19.pdf. [Last accessed on 2020 Mar 11].  Back to cited text no. 13
    
14.
Adaptive Platform Trials Coalition. Adaptive platform trials: Definition, design, conduct and reporting considerations. Nat Rev Drug Discov 2019;18:797-807.  Back to cited text no. 14
    



 
 
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