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Detection of significant antiviral drug effects on COVID-19 with reasonable sample sizes in randomized controlled trials : a modeling study

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Iwanami, Shoya, Ejima, Keisuke, Kim, Kwang Su, Noshita, Koji, Fujita, Yasuhisa, Miyazaki, Taiga, Kohno, Shigeru, Miyazaki, Yoshitsugu, Morimoto, Shimpei, Nakaoka, Shinji et al.
(2021) Detection of significant antiviral drug effects on COVID-19 with reasonable sample sizes in randomized controlled trials : a modeling study. PLoS Medicine, 18 (7). e1003660. doi:10.1371/journal.pmed.1003660 ISSN 1549-1277.

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Official URL: https://doi.org/10.1371/journal.pmed.1003660

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Abstract

Background
Development of an effective antiviral drug for Coronavirus Disease 2019 (COVID-19) is a global health priority. Although several candidate drugs have been identified through in vitro and in vivo models, consistent and compelling evidence from clinical studies is limited. The lack of evidence from clinical trials may stem in part from the imperfect design of the trials. We investigated how clinical trials for antivirals need to be designed, especially focusing on the sample size in randomized controlled trials.

Methods and findings
A modeling study was conducted to help understand the reasons behind inconsistent clinical trial findings and to design better clinical trials. We first analyzed longitudinal viral load data for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) without antiviral treatment by use of a within-host virus dynamics model. The fitted viral load was categorized into 3 different groups by a clustering approach. Comparison of the estimated parameters showed that the 3 distinct groups were characterized by different virus decay rates (p-value < 0.001). The mean decay rates were 1.17 d−1 (95% CI: 1.06 to 1.27 d−1), 0.777 d−1 (0.716 to 0.838 d−1), and 0.450 d−1 (0.378 to 0.522 d−1) for the 3 groups, respectively. Such heterogeneity in virus dynamics could be a confounding variable if it is associated with treatment allocation in compassionate use programs (i.e., observational studies).

Subsequently, we mimicked randomized controlled trials of antivirals by simulation. An antiviral effect causing a 95% to 99% reduction in viral replication was added to the model. To be realistic, we assumed that randomization and treatment are initiated with some time lag after symptom onset. Using the duration of virus shedding as an outcome, the sample size to detect a statistically significant mean difference between the treatment and placebo groups (1:1 allocation) was 13,603 and 11,670 (when the antiviral effect was 95% and 99%, respectively) per group if all patients are enrolled regardless of timing of randomization. The sample size was reduced to 584 and 458 (when the antiviral effect was 95% and 99%, respectively) if only patients who are treated within 1 day of symptom onset are enrolled. We confirmed the sample size was similarly reduced when using cumulative viral load in log scale as an outcome.

We used a conventional virus dynamics model, which may not fully reflect the detailed mechanisms of viral dynamics of SARS-CoV-2. The model needs to be calibrated in terms of both parameter settings and model structure, which would yield more reliable sample size calculation.

Conclusions
In this study, we found that estimated association in observational studies can be biased due to large heterogeneity in viral dynamics among infected individuals, and statistically significant effect in randomized controlled trials may be difficult to be detected due to small sample size. The sample size can be dramatically reduced by recruiting patients immediately after developing symptoms. We believe this is the first study investigated the study design of clinical trials for antiviral treatment using the viral dynamics model.

Item Type: Journal Article
Subjects: R Medicine > R Medicine (General)
R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine
R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Science, Engineering and Medicine > Science > Mathematics
Library of Congress Subject Headings (LCSH): Clinical trials -- Design, Drugs -- Testing, COVID-19 (Disease) -- Treatment, Antiviral agents -- Development
Journal or Publication Title: PLoS Medicine
Publisher: Public Library of Science
ISSN: 1549-1277
Official Date: 6 July 2021
Dates:
DateEvent
6 July 2021Published
18 May 2021Accepted
Volume: 18
Number: 7
Article Number: e1003660
DOI: 10.1371/journal.pmed.1003660
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 20 May 2021
Date of first compliant Open Access: 13 July 2021
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
JP19J12319[JSPS] Japan Society for the Promotion of Sciencehttp://dx.doi.org/10.13039/501100001691
JP18KT0018[JSPS] Japan Society for the Promotion of Sciencehttp://dx.doi.org/10.13039/501100001691
JP18H01139[JSPS] Japan Society for the Promotion of Sciencehttp://dx.doi.org/10.13039/501100001691
JP16H04845[JSPS] Japan Society for the Promotion of Sciencehttp://dx.doi.org/10.13039/501100001691
JP17H04085[JSPS] Japan Society for the Promotion of Sciencehttp://dx.doi.org/10.13039/501100001691
JP18K18146[JSPS] Japan Society for the Promotion of Sciencehttp://dx.doi.org/10.13039/501100001691
JP20H05042[JSPS] Japan Society for the Promotion of Sciencehttp://dx.doi.org/10.13039/501100001691
JP19H04839[JSPS] Japan Society for the Promotion of Sciencehttp://dx.doi.org/10.13039/501100001691
JP18H05103[JSPS] Japan Society for the Promotion of Sciencehttp://dx.doi.org/10.13039/501100001691
JP19gm1310002Japan Agency for Medical Research and Developmenthttp://dx.doi.org/10.13039/100009619
JP20wm0325007h0001Japan Agency for Medical Research and Developmenthttp://dx.doi.org/10.13039/100009619
JP20wm0325004s0201Japan Agency for Medical Research and Developmenthttp://dx.doi.org/10.13039/100009619
JP20wm0325012s0301Japan Agency for Medical Research and Developmenthttp://dx.doi.org/10.13039/100009619
JP20wm0325015s0301Japan Agency for Medical Research and Developmenthttp://dx.doi.org/10.13039/100009619
JP19fk0410023s0101Japan Agency for Medical Research and Developmenthttp://dx.doi.org/10.13039/100009619
JP19fk0108050h0003Japan Agency for Medical Research and Developmenthttp://dx.doi.org/10.13039/100009619
JP19fk0108156h0001Japan Agency for Medical Research and Developmenthttp://dx.doi.org/10.13039/100009619
JP20fk0108140s0801Japan Agency for Medical Research and Developmenthttp://dx.doi.org/10.13039/100009619
JP20fk0108413s0301Japan Agency for Medical Research and Developmenthttp://dx.doi.org/10.13039/100009619
JP19fk0210036h0502Japan Agency for Medical Research and Developmenthttp://dx.doi.org/10.13039/100009619
JP19fk0210036j0002Japan Agency for Medical Research and Developmenthttp://dx.doi.org/10.13039/100009619
JP19fk0310114h0103Japan Agency for Medical Research and Developmenthttp://dx.doi.org/10.13039/100009619
JP19fk0310114j0003Japan Agency for Medical Research and Developmenthttp://dx.doi.org/10.13039/100009619
JP19fk0310101j1003Japan Agency for Medical Research and Developmenthttp://dx.doi.org/10.13039/100009619
JP19fk0310103j0203Japan Agency for Medical Research and Developmenthttp://dx.doi.org/10.13039/100009619
MIRAIJapan Science and Technology Agencyhttp://dx.doi.org/10.13039/501100002241
JPMJMS2021Japan Science and Technology Agencyhttp://dx.doi.org/10.13039/501100002241
UNSPECIFIEDMitsui Sumitomo Insurance Welfare Foundationhttp://dx.doi.org/10.13039/100008734
UNSPECIFIEDShin-Nihon of Advanced Medical ResearchUNSPECIFIED
UNSPECIFIEDSuzuken Memorial Foundationhttp://dx.doi.org/10.13039/100007434
UNSPECIFIEDLife Science Foundation of Japanhttp://dx.doi.org/10.13039/501100012630
UNSPECIFIEDSecom Science and Technology Foundationhttp://dx.doi.org/10.13039/501100004298
UNSPECIFIEDJapan Prize Foundationhttp://dx.doi.org/10.13039/501100004016
UNSPECIFIEDDaiwa Securities Health Foundationhttp://dx.doi.org/10.13039/501100005928
UNSPECIFIEDYasuda Memorial Medical Foundationhttp://dx.doi.org/10.13039/501100008673
UNSPECIFIEDSmoking Research Foundationhttp://dx.doi.org/10.13039/501100004330
UNSPECIFIEDTakeda Science Foundationhttp://dx.doi.org/10.13039/100007449
PHY-2031756National Science Foundationhttp://dx.doi.org/10.13039/501100008982
R01-OD011095National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01-AI028433National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
UNSPECIFIEDLos Alamos National Laboratoryhttp://dx.doi.org/10.13039/100008902
3U24GM132013-02S2National Institute of General Medical Scienceshttp://dx.doi.org/10.13039/100000057
UNSPECIFIEDMeiji Yasuda Life Foundation of Health and Welfarehttp://dx.doi.org/10.13039/501100008882
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