{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T20:38:51Z","timestamp":1774039131126,"version":"3.50.1"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T00:00:00Z","timestamp":1683590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1163282"],"award-info":[{"award-number":["1163282"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>We proposed a Phase I dose escalation trial to assess the safety of allogeneic human amniotic epithelial cells (hAECs) in stroke patients with a view to informing the design for a Phase II trial.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The design is based on 3 + 3 dose escalation design with additional components for measuring MR signal of efficacy as well as the effect of hAECs (2\u20138 \u00d7 10<jats:sup>6<\/jats:sup>\/kg, i.v.) on preventing immunosuppression after stroke.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Eight patients (six males) were recruited within 24 h of ischemic stroke onset and were infused with hAECs. We were able to increase the dose of hAECs to 8 \u00d7 10<jats:sup>6<\/jats:sup> cells\/kg (2 \u00d7 10<jats:sup>6<\/jats:sup>\/kg, <jats:italic>n<\/jats:italic> = 3; 4 \u00d7 10<jats:sup>6<\/jats:sup>\/kg, <jats:italic>n<\/jats:italic> = 3; 8 \u00d7 10<jats:sup>6<\/jats:sup>\/kg, <jats:italic>n<\/jats:italic> = 2). The mean age is 68.0 \u00b1 10.9 (mean \u00b1 SD). The frequencies of hypertension and hyperlipidemia were 87.5%, diabetes was 37.5%, atrial fibrillation was 50%, ischemic heart disease was 37.5% and ever-smoker was 25%. Overall, baseline NIHSS was 7.5 \u00b1 3.1, 7.8 \u00b1 7.2 at 24 h, and 4.9 \u00b1 5.4 at 1 week (<jats:italic>n<\/jats:italic> = 8). The modified Rankin scale at 90 days was 2.1 \u00b1 1.2. Supplemental oxygen was given in five patients during hAEC infusion. Using pre-defined criteria, two serious adverse events occurred. One patient developed recurrent stroke and another developed pulmonary embolism whilst in rehabilitation. For the last four patients, infusion of hAECs was split across separate infusions on subsequent days to reduce the risk for fluid overload.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our Phase I trial demonstrates that a maximal dose of 2 \u00d7 10<jats:sup>6<\/jats:sup>\/kg hAECs given intravenously each day over 2 days (a total of 4 \u00d7 10<jats:sup>6<\/jats:sup>\/kg) is safe and optimal for use in a Phase II trial.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical trial registration<\/jats:title><jats:p><jats:ext-link>ClinicalTrials.gov<\/jats:ext-link>, identifier ACTRN12618000076279P.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnins.2023.1153231","type":"journal-article","created":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T04:31:03Z","timestamp":1683606663000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Phase I trial outcome of amnion cell therapy in patients with ischemic stroke (I-ACT)"],"prefix":"10.3389","volume":"17","author":[{"given":"Thanh G.","family":"Phan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Lim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siow T.","family":"Chan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah","family":"McDonald","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Poh-Yi","family":"Gan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shenpeng R.","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liz J.","family":"Barreto Arce","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason","family":"Vuong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tharani","family":"Thirugnanachandran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Clissold","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Ly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaloo","family":"Singhal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie Veronic","family":"Hervet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyun Ah","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grant R.","family":"Drummond","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Euan M.","family":"Wallace","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher G.","family":"Sobey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1486","DOI":"10.1001\/jamaneurol.2020.3362","article-title":"Trends in reperfusion therapy for in-hospital ischemic stroke in the endovascular therapy era.","volume":"77","author":"Akbik","year":"2020","journal-title":"JAMA Neurol."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2012.00066","article-title":"Post-stroke inflammation and the potential efficacy of novel stem cell therapies: focus on amnion epithelial cells.","volume":"6","author":"Broughton","year":"2013","journal-title":"Front. Cell Neurosci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1161\/STROKEAHA.119.027569","article-title":"Dabigatran treatment of acute noncardioembolic ischemic stroke.","volume":"51","author":"Butcher","year":"2020","journal-title":"Stroke"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2003","DOI":"10.1007\/s00415-009-5228-x","article-title":"C-reactive protein in the very early phase of acute ischemic stroke: association with poor outcome and death.","volume":"256","author":"den Hertog","year":"2009","journal-title":"J. Neurol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1346","DOI":"10.4103\/1673-5374.235223","article-title":"Amnion epithelial cells\u2014a novel therapy for ischemic stroke?","volume":"13","author":"Evans","year":"","journal-title":"Neural Regen. Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1161\/STROKEAHA.117.019136","article-title":"Acute or delayed systemic administration of human amnion epithelial cells improves outcomes in experimental stroke.","volume":"49","author":"Evans","year":"","journal-title":"Stroke"},{"key":"B7","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/S1474-4422(21)00252-0","article-title":"Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the global burden of disease study 2019.","volume":"20","year":"2021","journal-title":"Lancet Neurol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1016\/S1474-4422(17)30046-7","article-title":"Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (masters): a randomised, double-blind, placebo-controlled, phase 2 trial.","volume":"16","author":"Hess","year":"2017","journal-title":"Lancet Neurol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"878","DOI":"10.1016\/S0140-6736(20)30258-0","article-title":"Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (escape-na1): a multicentre, double-blind, randomised controlled trial.","volume":"395","author":"Hill","year":"2020","journal-title":"Lancet"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1704","DOI":"10.1161\/STROKEAHA.108.537613","article-title":"Results of the MRI substudy of the intravenous magnesium efficacy in stroke trial.","volume":"40","author":"Kidwell","year":"2009","journal-title":"Stroke"},{"key":"B11","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1002\/sctm.18-0079","article-title":"First-in-human administration of allogeneic amnion cells in premature infants with bronchopulmonary dysplasia: a safety study.","volume":"7","author":"Lim","year":"2018","journal-title":"Stem Cells Transl. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1111\/rssc.12089","article-title":"Bayesian optimal interval designs for phase i clinical trials.","volume":"64","author":"Liu","year":"2015","journal-title":"J. R. Stat. Soc. Ser. C"},{"key":"B13","doi-asserted-by":"publisher","first-page":"2521","DOI":"10.1161\/01.STR.0000239696.61545.4b","article-title":"Proof-of-principle phase II MRI studies in stroke: sample size estimates from dichotomous and continuous data.","volume":"37","author":"MR Stroke Collaborative Group","year":"2006","journal-title":"Stroke"},{"key":"B14","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1136\/jnnp-2019-322515","article-title":"Intracerebral implantation of human neural stem cells and motor recovery after stroke: multicentre prospective single-arm study (pisces-2).","volume":"91","author":"Muir","year":"2020","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"B15","doi-asserted-by":"publisher","first-page":"33","DOI":"10.2307\/2531628","article-title":"Continual reassessment method: a practical design for phase 1 clinical trials in cancer.","volume":"46","author":"O\u2019Quigley","year":"1990","journal-title":"Biometrics"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1001\/archneurol.2009.259","article-title":"Heterogeneity in infarct patterns and clinical outcomes following internal carotid artery occlusion.","volume":"66","author":"Phan","year":"2009","journal-title":"Arch. Neurol."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2019.00016","article-title":"Stroke severity versus dysphagia screen as driver for post-stroke pneumonia.","volume":"10","author":"Phan","year":"2019","journal-title":"Front. Neurol."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2018.00198","article-title":"Phase 1 trial of amnion cell therapy for ischemic stroke.","volume":"9","author":"Phan","year":"2018","journal-title":"Front. Neurol."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.113.000372","article-title":"Pulmonary embolism in ischemic stroke: clinical presentation, risk factors, and outcome.","volume":"2","author":"Pongmoragot","year":"2013","journal-title":"J. Am. Heart Assoc."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1161\/01.STR.0000170641.01047.cc","article-title":"A matrix metalloproteinase protein array reveals a strong relation between mmp-9 and mmp-13 with diffusion-weighted image lesion increase in human stroke.","volume":"36","author":"Rosell","year":"2005","journal-title":"Stroke"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1161\/STROKEAHA.107.500868","article-title":"Mmp-9-positive neutrophil infiltration is associated to blood-brain barrier breakdown and basal lamina type iv collagen degradation during hemorrhagic transformation after human ischemic stroke.","volume":"39","author":"Rosell","year":"2008","journal-title":"Stroke"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1001\/jama.2016.13647","article-title":"Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: a meta-analysis.","volume":"316","author":"Saver","year":"2016","journal-title":"JAMA."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1817","DOI":"10.1161\/STROKEAHA.116.012995","article-title":"Clinical outcomes of transplanted modified bone marrow-derived mesenchymal stem cells in stroke: a phase 1\/2a study.","volume":"47","author":"Steinberg","year":"2016","journal-title":"Stroke"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.699153","article-title":"Predictors of early and late infarct growth in defuse 3.","volume":"12","author":"Tate","year":"2021","journal-title":"Front. Neurol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1002\/1531-8249(200011)48:5<713::AID-ANA4>3.0.CO;2-#","article-title":"Effect of citicoline on ischemic lesions as measured by diffusion-weighted magnetic resonance imaging. Citicoline 010 investigators.","volume":"48","author":"Warach","year":"2000","journal-title":"Ann. Neurol."}],"updated-by":[{"DOI":"10.3389\/fnins.2023.1237920","type":"corrigendum","label":"Corrigendum","source":"publisher","updated":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T00:00:00Z","timestamp":1690761600000}}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2023.1153231\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T22:35:44Z","timestamp":1690842944000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2023.1153231\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,9]]},"references-count":25,"alternative-id":["10.3389\/fnins.2023.1153231"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2023.1153231","relation":{"corrigendum":[{"id-type":"doi","id":"10.3389\/fnins.2023.1237920","asserted-by":"object"}]},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,9]]},"article-number":"1153231"}}