key: cord-1050364-mjaj5f3d
authors: Boserup, Brad; McKenney, Mark; Elkbuli, Adel
title: An overview of current COVID-19 clinical trials and ethical considerations editorial
date: 2020-08-29
journal: Ann Med Surg (Lond)
DOI: 10.1016/j.amsu.2020.08.041
sha: 7104e0010bb75164f317cf94befa1fbd9ceb2de8
doc_id: 1050364
cord_uid: mjaj5f3d

Not applicable.

The causative agent of the COVID-19 pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a highly contagious RNA virus that has spread rapidly since the initial outbreak in December 2019. By August 25, 2020, there were 5,715,567 cases and 176,617 deaths in the United States (US) alone in the absence of any Food and Drug Administration (FDA) approved drugs to treat COVID-19. 1 However, as of August 25, 2020 there were 2,103 clinical trials reported from numerous national and international trial registry sites spanning 96 countries ( Figure 1 ). 2 Some of the treatment options under investigation with the greatest number of trials at the time of writing included hydroxychloroquine or chloroquine, alternative therapies, plasma-based therapy, traditional Chinese medicines and lopinavir-ritonavir ( Figure 2 ).

Chloroquine and hydroxychloroquine are known to have effects against several RNA viruses such as Zika and chikungunya and have exhibited an ability to inhibit SARS-CoV-2 in vitro. 3, 4 Additionally, the anti-inflammatory properties of chloroquine and hydroxychloroquine may control the effects of cytokine storm seen during late stages of COVID-19 and mitigate associated tissue damge. 5 The results of one open-label non-randomized trial in France, involving 36 COVID-19 patients, found that hydroxychloroquine use was associated with significantly improved outcomes compared to controls. 6 The study found that 70% of patients treated with hydroxychloroquine had negative PCR nasopharyngeal samples at day 6 compared with 12.5% in the control group. 6 However, despite promising results, this study has since received criticisms regarding its methodology. A randomized clinical trial in Wuhan, China that included 62 patients with COVID-19, found that the use of hydroxychloroquine was associated with significantly reduced time to clinical recovery, cough remission time, body temperature recovery time, and reduced progression to severe disease (this study has yet to undergo peer review). 7 In contrast, an open-label randomized trial in China that included 30 patients, did not find a significant difference at day 7 in viral clearance between the hydroxychloroquine treatment group and the control group. 8 Therefore, despite a large number of clinical trials underway to evaluate the efficacy of hydroxychloroquine or chloroquine in the treatment of COVID-19, there is currently an insufficient amount of published data to advocate for or against use.

Lopinavir-ritonavir is a combination protease inhibitor originally used for HIV treatment and prophylaxis, which has in vitro activity against SARS-CoV. 9 However, the clinical trial data available examining the use of lopinavir-ritonavir in the treatment of COVID-19 has shown it J o u r n a l P r e -p r o o f has little to no benefit in the treatment of COVID-19. One open-label randomized controlled trial in China, with 199 patients with COVID-19, found that the use of lopinavir-ritonavir was not associated with any difference in time to clinical improvement compared to standard care. 10 These results are understandable since lopinavir-ritonavir was originally designed to fit the HIV protease C2-symmetric binding pocket which is not present in SARS-CoV-2 proteases. 11 Additionally, the nucleoside analog favipiravir has recently been shown to be more effective than lopinavir-ritonavir. An open-label non-randomized comparative control trial in China that included 80 patients found that use of favipiravir was associated with significantly shorter viral clearance times, and significantly improved chest imaging compared to the use of lopinavirritonavir. 12 The improved efficacy of favipiravir versus lopinavir-ritonavir is likely due to its ability to act as a chain terminator and inhibit viral RNA polymerase. 13 Similarly, the nucleotide analog remdesivir, which also inhibits viral RNA polymerase has recently garnered a great deal of interest following the release of preliminary data from the Adaptive COVID-19 Treatment Trial. 14 This randomized, double-blind, placebo-controlled trial that included 1059 patients with COVID-19 found that the use of remdesivir was associated with faster recovery times (11 days versus 15 days with placebo) and reduced 14-day mortality rates (7.1% versus 11.9% with placebo). 15 Lastly, some other potentially useful treatment modalities include the use of convalescent plasma therapy and IL-6 inhibitors. Thus, despite a large number of ongoing clinical trials, the results from most are still pending, and there is currently still a paucity of quality information to guide clinical decision making. However, hundreds of trials are currently recruiting participants to investigate other potential treatment options, and more information from ongoing trials should become available in the coming months.

Amidst the fervor surrounding the development of new COVID-19 treatments, it is paramount that researchers maintain data integrity, especially given several recent high-profile retractions. These recent events highlight the need for further data oversite to maintain the integrity of new evidence. Furthermore, it is important that researchers also consider the ethical implications surrounding the emergency acceleration of clinical trials and approval processes. Lopinavir/ritonavir, and alternative therapies. • Newer agents such as remdesivir appear to provide clinical benefit, however, despite many ongoing clinical trials, there is still a lack of definitive evidence to guide clinical decision making.

• Given the rapidly evolving COVID-19 clinical trial landscape, it is vital that the US drugevaluation process is not jeopardized with regard to safety, efficacy, and credibility.

J o u r n a l P r e -p r o o f

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Current and future use of chloroquine and hydroxychloroquine in infectious, immune, neoplastic, and neurological diseases: a minireview

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)

Is hydroxychloroquine beneficial for COVID-19 patients?

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial

A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19)

Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings

A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19

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Favipiravir, an anti-influenza drug against life-threatening RNA virus infections

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Remdesivir for the Treatment of Covid-19 -Preliminary Report

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Please enter the name of the registry, the hyperlink to the registration and the unique identifying number of the study. You can register your research at http://www.researchregistry.com to obtain your UIN if you have not already registered your study. This is mandatory for human studies only.1. Name of the registry: 2. Unique Identifying number or registration ID:3. Hyperlink to the registration (must be publicly accessible):Not applicable-no human subjects or research participants' data were utilized or collected

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