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

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dc.contributor.author Stevenson, Nathan J.
dc.contributor.author Boylan, Geraldine B.
dc.contributor.author Hellström-Westas, Lena
dc.contributor.author Vanhatalo, Sampsa
dc.date.accessioned 2016-12-09T12:15:24Z
dc.date.available 2016-12-09T12:15:24Z
dc.date.issued 2016-11-08
dc.identifier.citation Stevenson, 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.0165693 en
dc.identifier.volume 11 en
dc.identifier.issued 11 en
dc.identifier.startpage 1 en
dc.identifier.endpage 14 en
dc.identifier.issn 1932-6203
dc.identifier.uri http://hdl.handle.net/10468/3367
dc.identifier.doi 10.1371/journal.pone.0165693
dc.description.abstract Neonatal 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.sponsorship Science 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.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Public Library of Science en
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.uri https://creativecommons.org/licenses/by/4.0/ en
dc.subject Hypoxic-ischemic encephalopathy en
dc.subject Electrographic seizures en
dc.subject Hypothermia en
dc.subject Burden en
dc.subject EEG en
dc.subject Phenobarbitone en
dc.subject Lidocaine en
dc.subject Efficacy en
dc.title Treatment trials for neonatal seizures: the effect of design on sample size en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Geraldine Boylan, Medicine , University College Cork, Cork, Ireland. +353-21-490-3000 Email: g.boylan@ucc.ie en
dc.internal.availability Full text available en
dc.date.updated 2016-12-09T11:54:30Z
dc.description.version Published Version en
dc.internal.rssid 375019505
dc.internal.wokid WOS:000387615200028
dc.contributor.funder Horizon 2020 en
dc.contributor.funder Science Foundation Ireland en
dc.contributor.funder Suomen Akatemia en
dc.contributor.funder Seventh Framework Programme en
dc.contributor.funder Health Research Board en
dc.contributor.funder Wellcome Trust en
dc.contributor.funder Sigrid Jusélius Foundation
dc.description.status Peer reviewed en
dc.identifier.journaltitle PLoS ONE en
dc.internal.copyrightchecked Yes en
dc.internal.licenseacceptance Yes en
dc.internal.IRISemailaddress g.boylan@ucc.ie en
dc.identifier.articleid e0165693
dc.relation.project info:eu-repo/grantAgreement/EC/H2020::MSCA-IF-EF-ST/656131/EU/An analyzer for preterm EEG/APE en
dc.relation.project info:eu-repo/grantAgreement/EC/FP7::SP1::HEALTH/241479/EU/Treatment of NEonatal seizures with Medication Off-patent: evaluation of efficacy and safety of bumetanide/NEMO en


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© 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. Except where otherwise noted, this item's license is described as © 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.
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