Design and analysis of crossover trials for absorbing binary endpoints

Biometrics
Martha Nason, Dean Follmann

Abstract

The crossover is a popular and efficient trial design used in the context of patient heterogeneity to assess the effect of treatments that act relatively quickly and whose benefit disappears with discontinuation. Each patient can serve as her own control as within-individual treatment and placebo responses are compared. Conventional wisdom is that these designs are not appropriate for absorbing binary endpoints, such as death or HIV infection. We explore the use of crossover designs in the context of these absorbing binary endpoints and show that they can be more efficient than the standard parallel group design when there is heterogeneity in individuals' risks. We also introduce a new two-period design where first period "survivors" are rerandomized for the second period. This design combines the crossover design with the parallel design and achieves some of the efficiency advantages of the crossover design while ensuring that the second period groups are comparable by randomization. We discuss the validity of the new designs and evaluate both a mixture model and a modified Mantel-Haenszel test for inference. The mixture model assumes no carryover or period effects while the Mantel-Haenszel approach conditions out period effec...Continue Reading

References

Jun 13, 2003·The New England Journal of Medicine·John I GallinSteven M Holland
Mar 8, 2007·Nature Medicine·Natasha Bolognesi
Dec 28, 2007·The New England Journal of Medicine·Robert Steinbrook

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Citations

Mar 23, 2013·Biostatistics·John N S Matthews, Robin Henderson
Aug 2, 2011·Statistics in Medicine·Anastasia IvanovaDavid A Schoenfeld
Oct 17, 2014·Pharmaceutical Statistics·Andrew J Dunning, John Reeves
Aug 4, 2016·BMC Medical Research Methodology·S Gwynn Sturdevant, Thomas Lumley
Nov 7, 2015·BMC Medical Research Methodology·Brennan C KahanTim P Morris
Jul 1, 2011·Statistical Methods in Medical Research·Jozefien Buyze, Els Goetghebeur
Dec 7, 2011·Statistical Methods in Medical Research·Anastasia Ivanova, Roy N Tamura
Feb 21, 2018·Statistics in Medicine·Rachel Kloss SilvermanJason Fine
Jul 17, 2018·Statistics in Medicine·Boxian WeiKelley M Kidwell
Oct 19, 2017·HIV Clinical Trials·Amy CutrellRobert L Cuffe
Oct 23, 2019·Statistics in Medicine·Chathura SiriwardhanaSomnath Datta
May 1, 2021·Statistics in Medicine·Jonathan Fintzi, Dean Follmann
May 18, 2021·Contemporary Clinical Trials Communications·S Gwynn Sturdevant, Thomas Lumley

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