Treatment trials for neonatal seizures: the effect of design on sample size

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dc.contributor.authorStevenson, Nathan J.
dc.contributor.authorBoylan, Geraldine B.
dc.contributor.authorHellström-Westas, Lena
dc.contributor.authorVanhatalo, Sampsa
dc.contributor.funderHorizon 2020en
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderSuomen Akatemiaen
dc.contributor.funderSeventh Framework Programmeen
dc.contributor.funderHealth Research Boarden
dc.contributor.funderWellcome Trusten
dc.contributor.funderSigrid Jusélius Foundation
dc.date.accessioned2016-12-09T12:15:24Z
dc.date.available2016-12-09T12:15:24Z
dc.date.issued2016-11-08
dc.date.updated2016-12-09T11:54:30Z
dc.description.abstractNeonatal seizures are common in the neonatal intensive care unit. Clinicians treat these seizures with several anti-epileptic drugs (AEDs) to reduce seizures in a neonate. Current AEDs exhibit sub-optimal efficacy and several randomized control trials (RCT) of novel AEDs are planned. The aim of this study was to measure the influence of trial design on the required sample size of a RCT. We used seizure time courses from 41 term neonates with hypoxic ischaemic encephalopathy to build seizure treatment trial simulations. We used five outcome measures, three AED protocols, eight treatment delays from seizure onset (Td) and four levels of trial AED efficacy to simulate different RCTs. We performed power calculations for each RCT design and analysed the resultant sample size. We also assessed the rate of false positives, or placebo effect, in typical uncontrolled studies. We found that the false positive rate ranged from 5 to 85% of patients depending on RCT design. For controlled trials, the choice of outcome measure had the largest effect on sample size with median differences of 30.7 fold (IQR: 13.7–40.0) across a range of AED protocols, Td and trial AED efficacy (p<0.001). RCTs that compared the trial AED with positive controls required sample sizes with a median fold increase of 3.2 (IQR: 1.9–11.9; p<0.001). Delays in AED administration from seizure onset also increased the required sample size 2.1 fold (IQR: 1.7–2.9; p<0.001). Subgroup analysis showed that RCTs in neonates treated with hypothermia required a median fold increase in sample size of 2.6 (IQR: 2.4–3.0) compared to trials in normothermic neonates (p<0.001). These results show that RCT design has a profound influence on the required sample size. Trials that use a control group, appropriate outcome measure, and control for differences in Td between groups in analysis will be valid and minimise sample size.en
dc.description.sponsorshipScience Foundation Ireland (Grant No. 12/RC/2272); Suomen Akatemia (Grant Nos. 276523 and 288220); Health Research Board (Principal Investigator Awards RP/2008/238); Wellcome Trust (Grant No. 085249)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleide0165693
dc.identifier.citationStevenson, N. J., Boylan, G. B., Hellström-Westas, L. and Vanhatalo, S. (2016) ‘Treatment trials for neonatal seizures: the effect of design on sample size’, PLoS ONE, 11(11), e0165693 (14pp). doi:10.1371/journal.pone.0165693en
dc.identifier.doi10.1371/journal.pone.0165693
dc.identifier.endpage14en
dc.identifier.issn1932-6203
dc.identifier.issued11en
dc.identifier.journaltitlePLoS ONEen
dc.identifier.startpage1en
dc.identifier.urihttps://hdl.handle.net/10468/3367
dc.identifier.volume11en
dc.language.isoenen
dc.publisherPublic Library of Scienceen
dc.relation.projectinfo:eu-repo/grantAgreement/EC/H2020::MSCA-IF-EF-ST/656131/EU/An analyzer for preterm EEG/APEen
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP1::HEALTH/241479/EU/Treatment of NEonatal seizures with Medication Off-patent: evaluation of efficacy and safety of bumetanide/NEMOen
dc.rights© 2016, Stevenson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectHypoxic-ischemic encephalopathyen
dc.subjectElectrographic seizuresen
dc.subjectHypothermiaen
dc.subjectBurdenen
dc.subjectEEGen
dc.subjectPhenobarbitoneen
dc.subjectLidocaineen
dc.subjectEfficacyen
dc.titleTreatment trials for neonatal seizures: the effect of design on sample sizeen
dc.typeArticle (peer-reviewed)en
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