Research response to coronavirus disease 2019 needed better coordination and collaboration: a living mapping of registered trials

Objectives: Researchers worldwide are actively engaging in research activities to search for preventive and therapeutic interventions against coronavirus disease 2019 (COVID-19). Our aim was to describe the planning of randomized controlled trials (RCTs) in terms of timing related to the course of the COVID-19 epidemic and research question evaluated. Study Design and Setting: We performed a living mapping of RCTs registered in the WHO International Clinical Trials Registry Platform. We systematically search the platform every week for all RCTs evaluating preventive interventions and treatments for COVID-19 and created a publicly available interactive mapping tool at https://covid-nma.com to visualize all trials registered. Results: By August 12, 2020, 1,568 trials for COVID-19 were registered worldwide. Overall, the median ([Q1–Q3]; range) delay between the first case recorded in each country and the first RCT registered was 47 days ([33–67]; 15–163). For the 9 countries with the highest number of trials registered, most trials were registered after the peak of the epidemic (from 100% trials in Italy to 38% in the United States). Most trials evaluated treatments (1,333 trials; 85%); only 223 (14%) evaluated preventive strategies and 12 postacute period intervention. A total of 254 trials were planned to assess different regimens of hydroxychloroquine with an expected sample size of 110,883 patients. Conclusion: This living mapping analysis showed that COVID-19 trials have relatively small sample size with certain redundancy in research questions. Most trials were registered when the first peak of the pandemic has passed

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Correction: Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

International audienc