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Treatment Trials for Neonatal Seizures: The Effect of Design on Sample Size
Univ Coll Cork, Irish Ctr Fetal & Neonatal Translat Res, Cork, Ireland.;Univ Coll Cork, Dept Paediat & Child Hlth, Cork, Ireland.;Univ Helsinki, Dept Neurol Sci, Clinicum, Helsinki, Finland..
Univ Coll Cork, Irish Ctr Fetal & Neonatal Translat Res, Cork, Ireland.;Univ Coll Cork, Dept Paediat & Child Hlth, Cork, Ireland..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
Univ Helsinki, Cent Hosp, Dept Clin Neurophysiol, HUS Med Imaging Ctr, Helsinki, Finland.;Univ Helsinki, Dept Neurol Sci, Clinicum, Helsinki, Finland..
2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 11, article id e0165693Article in journal (Refereed) Published
Abstract [en]

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 (T-d) 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.

Place, publisher, year, edition, pages
2016. Vol. 11, no 11, article id e0165693
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-309807DOI: 10.1371/journal.pone.0165693ISI: 000387615200028PubMedID: 27824913OAI: oai:DiVA.org:uu-309807DiVA, id: diva2:1056540
Funder
EU, FP7, Seventh Framework Programme, FP7-HEALTH-2009-4.2-1 241479Wellcome trust
Available from: 2016-12-15 Created: 2016-12-07 Last updated: 2017-11-29Bibliographically approved

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