{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:04:58Z","timestamp":1789617898734,"version":"build-2803163510"},"reference-count":38,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T00:00:00Z","timestamp":1718150400000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T00:00:00Z","timestamp":1718150400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T00:00:00Z","timestamp":1718150400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K23NS114201"],"award-info":[{"award-number":["K23NS114201"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS102190"],"award-info":[{"award-number":["R01NS102190"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS102574"],"award-info":[{"award-number":["R01NS102574"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS107291"],"award-info":[{"award-number":["R01NS107291"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["CAREER DMS\u20102046880"],"award-info":[{"award-number":["CAREER DMS\u20102046880"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["IIS\u20102147061"],"award-info":[{"award-number":["IIS\u20102147061"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background\/objectives<\/jats:title>\n                    <jats:p>Epileptiform activity (EA), including seizures and periodic patterns, worsens outcomes in patients with acute brain injuries (e.g., aneurysmal subarachnoid hemorrhage [aSAH]). Randomized control trials (RCTs) assessing anti\u2010seizure interventions are needed. Due to scant drug efficacy data and ethical reservations with placebo utilization, and complex physiology of acute brain injury, RCTs are lacking or hindered by design constraints. We used a pharmacological model\u2010guided simulator to design and determine the feasibility of RCTs evaluating EA treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In a single\u2010center cohort of adults (age &gt;18) with aSAH and EA, we employed a mechanistic pharmacokinetic\u2010pharmacodynamic framework to model treatment response using observational data. We subsequently simulated RCTs for levetiracetam and propofol, each with three treatment arms mirroring clinical practice and an additional placebo arm. Using our framework, we simulated EA trajectories across treatment arms. We predicted discharge modified Rankin Scale as a function of baseline covariates, EA burden, and drug doses using a double machine learning model learned from observational data. Differences in outcomes across arms were used to estimate the required sample size.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Sample sizes ranged from 500 for levetiracetam 7\u2009mg\/kg versus placebo, to &gt;4000 for levetiracetam 15 versus 7\u2009mg\/kg to achieve 80% power (5% type I error). For propofol 1\u2009mg\/kg\/h versus placebo, 1200 participants were needed. Simulations comparing propofol at varying doses did not reach 80% power even at samples &gt;1200.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our simulations using drug efficacy show sample sizes are infeasible, even for potentially unethical placebo\u2010control trials. We highlight the strength of simulations with observational data to inform the null hypotheses and propose use of this simulation\u2010based RCT paradigm to assess the feasibility of future trials of anti\u2010seizure treatment in acute brain injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.52059","type":"journal-article","created":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T00:39:57Z","timestamp":1718239197000},"page":"1681-1690","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["How many patients do you need? Investigating trial designs for anti\u2010seizure treatment in acute brain injury patients"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1927-8646","authenticated-orcid":false,"given":"Harsh","family":"Parikh","sequence":"first","affiliation":[{"name":"Department of Biostatistics Johns Hopkins Bloomberg School of Public Health  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoqi","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Neurology Beth Israel Deaconess Medical Center  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh","family":"Amerineni","sequence":"additional","affiliation":[{"name":"Department of Neurology Massachusetts General Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3900-356X","authenticated-orcid":false,"given":"Eric S.","family":"Rosenthal","sequence":"additional","affiliation":[{"name":"Department of Neurology Massachusetts General Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4462-1020","authenticated-orcid":false,"given":"Alexander","family":"Volfovsky","sequence":"additional","affiliation":[{"name":"Department of Computer Science Duke University  Duke North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Rudin","sequence":"additional","affiliation":[{"name":"Department of Computer Science Duke University  Duke North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Brandon","family":"Westover","sequence":"additional","affiliation":[{"name":"Department of Neurology Beth Israel Deaconess Medical Center  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahar F.","family":"Zafar","sequence":"additional","affiliation":[{"name":"Department of Neurology Massachusetts General Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,12]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000281664.02615.6c"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e3181a00604"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-013-3149-8"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2016.4990"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2020.107037"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26161"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2589-7500(23)00088-2"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002281"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinph.2018.08.015"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12028-021-01387-x"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-022-06183-9"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.51478"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2115998"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/WNP.0000000000000801"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2010.09.011"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0165693"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25249"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1177\/0962280220975790"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2288-11-94"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cct.2021.106663"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1097\/WNP.0000000000000806"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12028\u2010016\u20100245"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24606"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2016.5325"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000063316.47591.b4"},{"key":"e_1_2_11_27_1","doi-asserted-by":"crossref","unstructured":"JingJ d'AngremontE ZafarS et\u00a0al.Rapid annotation of seizures and interictal\u2010ictal continuum eeg patterns. 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