Are large randomised controlled trials in severe sepsis and septic shock statistically disadvantaged by repeated inadvertent underestimates of required sample size?

BMJ Open
Joshua L C WongStephen J Brett

Abstract

We sought to understand why randomised controlled trials in septic shock have failed to demonstrate effectiveness in the face of improving overall outcomes for patients and seemingly promising results of early phase trials of interventions. We performed a retrospective analysis of large critical care trials of severe sepsis and septic shock. Data were collected from the primary trial manuscripts, prepublished statistical plans or by direct communication with corresponding authors. Critical care randomised control trials in severe sepsis and septic shock. 14 619 patients randomised in 13 trials published between 2005 and 2015, enrolling greater than 500 patients and powered to a primary outcome of mortality. Multiple interventions including the evaluation of treatment strategies and novel therapeutics. Our primary outcome measure was the difference between the anticipated and actual control arm mortality. Secondary analysis examined the actual effect size and the anticipated effect size employed in sample size calculation. In this post hoc analysis of 13 trials with 14 619 patients randomised, we highlight a global tendency to overestimate control arm mortality in estimating sample size (absolute difference 9.8%, 95% CI -14.7% t...Continue Reading

References

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Citations

Jul 12, 2019·Expert Review of Clinical Pharmacology·Jean-Louis Vincent, Yasser Sakr
Sep 8, 2020·Pharmaceutical Statistics·P M BrownErik Solligård
Jul 10, 2019·JAMA : the Journal of the American Medical Association·Jayshil J Patel, Paul A Bergl
Jul 10, 2019·JAMA : the Journal of the American Medical Association·Jan Bakker, Glenn Hernández
Jan 9, 2020·Journal of Proteome Research·Christelle DuboisFrançois Becher
Jul 16, 2021·Critical Care Medicine·George E PlopperTimothy G Buchman

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Clinical Trials Mentioned

NCT01598831

Software Mentioned

GraphPad Prism
ProCESS
Excel
R

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