The fragmented COVID-19 therapeutics research landscape: a living systematic review of clinical trial registrations evaluating priority pharmacological interventions.

<ns5:p><ns5:bold>Background:</ns5:bold> Many available medicines have been evaluated as potential repurposed treatments for coronavirus disease 2019 (COVID-19). We summarise the registered study landscape for 32 priority pharmacological treatments identified following consultation with external experts of the COVID-19 Clinical Research Coalition.</ns5:p><ns5:p> <ns5:bold>Methods:</ns5:bold> All eligible trial registry records identified by systematic searches of the World Health Organisation International Clinical Trials Registry Platform as of 26<ns5:sup>th</ns5:sup> May 2021 were reviewed and extracted. A descriptive summary of study characteristics was performed.</ns5:p><ns5:p> <ns5:bold>Results:</ns5:bold> We identified 1,314 registered studies that included at least one of the 32 priority pharmacological interventions. The majority (1,043, 79%) were randomised controlled trials (RCTs). The sample size of the RCTs identified was typically small (median (25<ns5:sup>th</ns5:sup>, 75<ns5:sup>th</ns5:sup> percentile) sample size = 140 patients (70, 383)), i.e. individually powered only to show very large effects. The most extensively evaluated medicine was hydroxychloroquine (418 registered studies). Other widely studied interventions were convalescent plasma (n=208), ritonavir (n=189) usually combined with lopinavir (n=181), and azithromycin (n=147). Very few RCTs planned to recruit participants in low-income countries (n=14; 1.3%). A minority of studies (348, 26%) indicated a willingness to share individual participant data. The living systematic review data are available at <ns5:ext-link xmlns:ns6="http://www.w3.org/1999/xlink" ext-link-type="uri" ns6:href="https://iddo.cognitive.city/cognitive/welcome">https://iddo.cognitive.city</ns5:ext-link></ns5:p><ns5:p> <ns5:bold>Conclusions:</ns5:bold> There are many registered studies planning to evaluate available medicines as potential repurposed treatments of COVID-19. Most of these planned studies are small, and therefore substantially underpowered for most relevant endpoints. Very few are large enough to have any chance of providing enough convincing evidence to change policies and practices. The sharing of individual participant data (IPD) from these studies would allow pooled IPD meta-analyses which could generate definitive conclusions, but most registered studies did not indicate that they were willing to share their data.</ns5:p>