key: cord-0312532-yh6r74k7 authors: Hirt, J.; Janiaud, P.; Hemkens, L. G. title: Randomized trials on non-pharmaceutical interventions for COVID-19 as of August 2021: a meta-epidemiological analysis date: 2021-08-30 journal: nan DOI: 10.1101/2021.08.20.21261687 sha: ef904517b8e24718f00835e6f9f9f498fdb70537 doc_id: 312532 cord_uid: yh6r74k7 Background: Numerous non-pharmaceutical interventions (NPIs) were taken worldwide to contain the spread of the COVID-19 pandemic. We aimed at providing an overview of randomized trials assessing NPIs to prevent COVID-19. Methods: We included all randomized trials assessing NPIs to prevent COVID-19 in any country and setting registered in ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform using the COVID-evidence platform (until 17 August 2021). We searched for corresponding publications in MEDLINE/PubMed, Google Scholar, the Living Overview of Evidence platform (L-OVE), and the Cochrane COVID-19 registry as well as for results posted in registries. Results: We identified 41 randomized trials. Of them, 11 were completed (26.8%) including 7 with published results. The 41 trials planned to recruit a median of 1,700 participants (IQR, 588 to 9,500, range 30 to 35,256,399) with a median planned duration of 8 months (IQR, 3 to 14, range 1 to 24). Most came from the United States (n=11, 26.8%). The trials mostly assessed protective equipment (n=11, 26.8%), COVID-19-related information and education programs (n=9, 22.0%), access to mass events under specific safety measures (n=5, 12.2%), testing and screening strategies (n=5, 12.2%), and hygiene management (n=5, 12.2%). Conclusions: Worldwide, 41 randomized trials assessing NPIs have been initiated with published results available to inform policy decisions for only 7 of them. A long-term research agenda including behavioral, environmental, social, and systems level interventions is urgently needed to guide policies and practices in the current and future public health emergencies. Numerous non-pharmaceutical interventions (NPIs) were taken worldwide to contain the COVID-19 pandemic. 1 NPIs are considered crucial to prevent infections, in particular for non-vaccinated populations. 2 Such interventions during COVID-19 include drastic social distancing and lockdown measures impacting billions of people. The need for randomized evidence on NPIs has been highlighted on numerous occasions [3] [4] [5] . However, no randomized trials assessing NPIs were initiated early in the pandemic 6 and it is likely their number have remained sparse. [7] [8] [9] We aimed to provide a systematic overview of the research agenda of randomized trials assessing NPIs to prevent COVID-19. A meta-epidemiological analysis was performed to collect the current trials on NPIs and to summarize their status and characteristics. We did not register this study or published a specific study protocol. We adapted PRISMA 2020 to provide a comprehensive study report, where applicable. 10 This meta-epidemiological analysis included all registered randomized trials assessing NPIs to prevent COVID-19 in any country and setting. We considered any NPIs as single measures or in combination involving, for example, information and education interventions, protective equipment, disinfection, social distancing, isolation, quarantine, testing, or community-wide containment strategies. We excluded interventions based on drugs, biologicals, vaccines, herbals, traditional medicine, and homeopathy. Trials assessing NPIs without any health outcome related to SARS-CoV-2-infections were excluded (e.g., interventions aiming to improve vaccination rates). We searched the COVID-evidence platform (www.covid-evidence.org) for eligible trials as of 17 August 2021. COVID-evidence is a freely available continuously updated database that contains information about worldwide planned, ongoing, and completed randomized trials on any intervention is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 30, 2021. ; https://doi.org/10.1101/2021.08.20.21261687 doi: medRxiv preprint and the selection of trials were done by one researcher (JH or PJ). Unclear cases were discussed and resolved within the study team (JH, PJ, LGH). One researcher (JH) extracted data on trial status, start to end date, country, setting, number of enrolled individuals and clusters, topic (details on NPIs and characteristics of the population), and design features (randomization unit, number of arms, outcome measurement). Extractions were tabulated and verified by two other researchers (PJ, LGH). Descriptive statistics using numbers and percentages were used. We used R (version 4.1). We identified 41 eligible randomized trials (Figure ; Table) Thanksgiving and Christmas with >35 million participants 12 , the shortest trial assessed the audience infection rate 8 days after an indoor music event. 13 A typical randomized trial on NPIs randomly allocated individuals (n=23, 56.1%), rather than clusters (n=18, 43.9%), to two comparison groups (n=38, 92.7%) and assessed a COVID-19-related primary outcome (n=33, 80.5%) that was laboratoryconfirmed (n=33, 80.5%). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 30, 2021. ; https://doi.org/10.1101/2021.08.20.21261687 doi: medRxiv preprint Worldwide, 41 randomized trials assessing NPIs have been initiated with published results available to inform policy decisions for only 7 of them. This is a tiny fraction of more than 4000 randomized trials on COVID-19 registered globally as of August 2021. 11 Given the unprecedented public health impact worldwide and the wide debates about benefits and harms of NPIs, this number seems disproportionate in light of other interventions that have been the focus of much more evaluation with randomized trials. For example, over 300 randomized trials included the highly debated hydroxychloroquine in their intervention arm 14 which has been found to be associated with increased mortality in COVID-19 patients. 15 The list of available treatments for COVID-19 is limited 16, 17 and with vaccination rates plateauing in many countries 18 , NPIs and their effectiveness will remain a central debate. Our analysis clearly indicates that randomized trials are generally feasible to assess the benefits and harms of NPIs during a pandemic situation, in a very short time using the most reliable method to provide reliable evidence for optimal health policy decision making. The World Health Organization (WHO) is committed to improving the evidence base on effectiveness of public health and social measures 19 , and this overview may inform further developments in this important area of evidence generation. This study is limited as our sample relies on accurate trial registration and reporting. We cannot exclude that some NPI randomized trials might have been missed because they were not registered, outcomes related to SARS-CoV-2-infections were incorrectly or not reported in the registries, or because of our single-reviewer screening approach. However, it is unlikely that we have been unaware of pertinent results of further NPI trials, given their substantial impact on current debates and scarcity of the evidence. Overall, during the first 18 months of the pandemic, the worldwide clinical research agenda failed to provide urgently needed evidence determining best strategies to prevent COVID-19 in schools, workplaces, nursing homes and other settings substantially affected. A long-term research agenda including behavioral, environmental, social, and systems level interventions is urgently needed to guide policies and practices in the current and future public health emergencies. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 30, 2021. ; https://doi.org/10.1101/2021.08.20.21261687 doi: medRxiv preprint World Health Organization. Overview of public health and social measures in the context of COVID-19: Interim guidance The Combined Effect of Vaccination and Nonpharmaceutical Public Health Interventions-Ending the COVID-19 Pandemic Preserving equipoise and performing randomised trials for COVID-19 social distancing interventions COVID-19: we need randomised trials of school closures A fiasco in the making? As the coronavirus pandemic takes hold, we are making decisions without reliable data The worldwide clinical trial research response to the COVID-19 pandemic -the first 100 days International travel-related control measures to contain the COVID-19 pandemic: a rapid review Quarantine alone or in combination with other public health measures to control COVID-19: a rapid review Impact of non-pharmaceutical interventions for reducing transmission of COVID-19: a systematic review and meta-analysis protocol Same-day SARS-CoV-2 antigen test screening in an indoor mass-gathering live music event: a randomised controlled trial. The Lancet Infectious Diseases Challenges and lessons learned from Covid-19 trialsshould we be doing clinical trials differently? Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials Emergency Use Authorization: Coronavirus Disease 2019 (COVID-19) EUA Information Treatments and vaccines for COVID-19 Vaccination burnout?: Delta variant spurs countries to speed up shots World Health Organization. Director-General's opening remarks at the media briefing on COVID Self-made gastroscope mask for patients (18- Abbreviations: GP = General practitioner; N/n = Number; n.r. = Not reported; t = Terminated early; w = Withdrawn (trial did and will never start). a For cluster randomized trials only. b Published as preprint results as of 19 August 2021. c Intervention was done twice (first on Thanksgiving, second on Christmas), numbers separated by semicolon for the first and second trial part. d Planned sample size was calculated by the mean of the reported minimum and maximum for number of participants (116,750 to 359,500) and clusters (934 and 2,876).