Most randomized comparisons of interventions in medicine use small or modest sample sizes. The need to conduct more large trials has long been proposed, particularly "mega-trials" (also called large simple trials) with over 10,000 participants1,2. These type of trials have been rare in the past, but there has been a renewed interest in recent years. Some mega-trials have found that certain interventions, like vitamin D supplementation, may not be as effective as previously thought3,4. The conduct of mega-trials may be facilitated by the advent of interest in pragmatic research5,6, new platforms that facilitate recruitment of participants7, and recognition of limitations of small trials. Therefore, it is very important to understand and compare the results of mega-trials to those of smaller trials on the same topic. Typically, the results of all available trials on a given topic are combined in meta-analyses. Meta-analyses of clinical trials are considered the cornerstone of evidence-based medicine and public health. However, there are concerns about the validity and accuracy of the process8. Most meta-analyses rarely include large trials and small trials have traditionally been considered more susceptible to biases, including more prominent selective reporting biases9,10. Additionally, previous literature comparing results of meta-analyses of small trials with subsequent large trials has shown contradicting results, with considerable variation on the extent of agreement or disagreement between the two types of evidence11-14. Previous work on the discrepancies between meta-analyses and larger trials results have identified several factors that may contribute to these differences, including different outcomes used to define agreement, event rates in the control group, trial quality and health outcomes under investigation11. An overarching limitation of previous work is that there is no clear consensus on what constitutes a "large trial". Typically, prior efforts that assessed the presence of small study effects has [...]
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