{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T04:26:06Z","timestamp":1775276766297,"version":"3.50.1"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T00:00:00Z","timestamp":1698883200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T00:00:00Z","timestamp":1698883200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG069930"],"award-info":[{"award-number":["R01AG069930"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["U24TR001609"],"award-info":[{"award-number":["U24TR001609"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Neurocrit Care"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Patients with acute spontaneous intracerebral hemorrhage (ICH) develop secondary neuroinflammation and cerebral edema that can further damage the brain and lead to increased risk of neurologic complications. Preclinical studies in animal models of acute brain injury have shown that a novel small-molecule drug candidate, MW01-6-189WH (MW189), decreases neuroinflammation and cerebral edema and improves functional outcomes. MW189 was also safe and well tolerated in phase 1 studies in healthy adults. The proof-of-concept phase 2a Biomarker and Edema Attenuation in IntraCerebral Hemorrhage\u00a0(BEACH) clinical trial is a first-in-patient, multicenter, randomized, double-blind, placebo-controlled trial. It is designed to determine the safety and tolerability of MW189 in patients with acute ICH, identify trends in potential mitigation of neuroinflammation and cerebral edema, and assess effects on functional outcomes. A total of 120 participants with nontraumatic ICH will be randomly assigned 1:1 to receive intravenous MW189 (0.25\u00a0mg\/kg) or placebo (saline) within 24\u00a0h of symptom onset and every 12\u00a0h for up to 5\u00a0days or until hospital discharge. The 120-participant sample size (60 per group) will allow testing of the null hypothesis of noninferiority with a tolerance limit of 12% and assuming a \u201cworst-case\u201d safety assumption of 10% rate of death in each arm with 10% significance and 80% power. The primary outcome is all-cause mortality at 7\u00a0days post randomization between treatment arms. Secondary end points include all-cause mortality at 30\u00a0days, perihematomal edema volume after symptom onset, adverse events, vital signs, pharmacokinetics of MW189, and inflammatory cytokine concentrations in plasma (and cerebrospinal fluid if available). Other exploratory end points are functional outcomes collected on days 30, 90, and 180. BEACH will provide important information about the utility of targeting neuroinflammation in ICH and will inform the design of future larger trials of acute central nervous system injury.<\/jats:p>","DOI":"10.1007\/s12028-023-01867-2","type":"journal-article","created":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T21:30:11Z","timestamp":1698960611000},"page":"807-815","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Clinical Trial Protocol for BEACH: A Phase 2a Study of MW189 in Patients with Acute Nontraumatic Intracerebral Hemorrhage"],"prefix":"10.1007","volume":"40","author":[{"given":"Radhika","family":"Avadhani","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wendy C.","family":"Ziai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard E.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W. Andrew","family":"Mould","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen","family":"Lane","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angeline","family":"Nanni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Iacobelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew F.","family":"Sharrock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren H.","family":"Sansing","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda J.","family":"Van Eldik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9536-4258","authenticated-orcid":false,"given":"Daniel F.","family":"Hanley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"on behalf of the BEACH trial consortium","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaron","family":"Lord","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Liptrap","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Zuccarello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Hatton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tarun","family":"Girotra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiffany","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin","family":"Mascitelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Magid-Bernstein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Babi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,11,2]]},"reference":[{"issue":"19","key":"1867_CR1","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1056\/NEJM200105103441907","volume":"344","author":"AI Qureshi","year":"2001","unstructured":"Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001;344(19):1450\u201360.","journal-title":"N Engl J Med"},{"issue":"9675","key":"1867_CR2","doi-asserted-by":"publisher","first-page":"1632","DOI":"10.1016\/S0140-6736(09)60371-8","volume":"373","author":"AI Qureshi","year":"2009","unstructured":"Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet. 2009;373(9675):1632\u201344.","journal-title":"Lancet"},{"issue":"1","key":"1867_CR3","doi-asserted-by":"publisher","first-page":"3","DOI":"10.5853\/jos.2016.00864","volume":"19","author":"SJ An","year":"2017","unstructured":"An SJ, Kim TJ, Yoon B-W. Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: an update. J Stroke. 2017;19(1):3\u201310.","journal-title":"J Stroke"},{"issue":"2","key":"1867_CR4","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/S1474-4422(09)70340-0","volume":"9","author":"CJ van Asch","year":"2010","unstructured":"van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010;9(2):167\u201376.","journal-title":"Lancet Neurol"},{"issue":"10","key":"1867_CR5","doi-asserted-by":"publisher","first-page":"e01113","DOI":"10.1002\/brb3.1113","volume":"8","author":"LR \u00d8ie","year":"2018","unstructured":"\u00d8ie LR, Madsbu MA, Solheim O, et al. Functional outcome and survival following spontaneous intracerebral hemorrhage: a retrospective population-based study. Brain Behav. 2018;8(10):e01113.","journal-title":"Brain Behav"},{"issue":"12","key":"1867_CR6","doi-asserted-by":"publisher","first-page":"1867","DOI":"10.1016\/j.jocn.2015.04.020","volume":"22","author":"E Camacho","year":"2015","unstructured":"Camacho E, LoPresti MA, Bruce S, et al. The role of age in intracerebral hemorrhages. J Clin Neurosci. 2015;22(12):1867\u201370.","journal-title":"J Clin Neurosci"},{"issue":"4","key":"1867_CR7","doi-asserted-by":"publisher","first-page":"1126","DOI":"10.1161\/STROKEAHA.111.644716","volume":"43","author":"M Stein","year":"2012","unstructured":"Stein M, Misselwitz B, Hamann GF, Scharbrodt W, Schummer DI, Oertel MF. Intracerebral hemorrhage in the very old: future demographic trends of an aging population. Stroke. 2012;43(4):1126\u20138.","journal-title":"Stroke"},{"issue":"15","key":"1867_CR8","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1212\/WNL.0000000000002015","volume":"85","author":"WMT Jolink","year":"2015","unstructured":"Jolink WMT, Klijn CJM, Brouwers PJAM, Kappelle LJ, Vaartjes I. Time trends in incidence, case fatality, and mortality of intracerebral hemorrhage. Neurology. 2015;85(15):1318\u201324.","journal-title":"Neurology"},{"issue":"2","key":"1867_CR9","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1007\/s12028-020-00916-4","volume":"33","author":"BM Hansen","year":"2020","unstructured":"Hansen BM, Ullman N, Muschelli J, et al. Relationship of white matter lesions with intracerebral hemorrhage expansion and functional outcome: MISTIE II and CLEAR III. Neurocrit Care. 2020;33(2):516\u201324.","journal-title":"Neurocrit Care"},{"key":"1867_CR10","doi-asserted-by":"crossref","unstructured":"Li Y, Cho S-M, Avadhani R, et al. Cerebral small vessel disease burden and association with post-surgical rebleeding and long-term outcome in intracerebral hemorrhage participants from the MISTIE III trial. Presented at: International Stroke Conference 2020; February 19\u201321, 2020; Los Angeles, CA.","DOI":"10.1161\/str.51.suppl_1.7"},{"issue":"56","key":"1867_CR11","doi-asserted-by":"publisher","first-page":"eab6279","DOI":"10.1126\/sciimmunol.abd6279","volume":"6","author":"MH Askenase","year":"2021","unstructured":"Askenase MH, Goods BA, Beatty HE, et al. Longitudinal transcriptomics define the stages of myeloid activation in the living human brain after intracerebral hemorrhage. Sci Immunol. 2021;6(56):eab6279.","journal-title":"Sci Immunol"},{"issue":"8","key":"1867_CR12","doi-asserted-by":"publisher","first-page":"1204","DOI":"10.1161\/CIRCRESAHA.121.319949","volume":"130","author":"J Magid-Bernstein","year":"2022","unstructured":"Magid-Bernstein J, Girard R, Polster S, et al. Cerebral hemorrhage: pathophysiology, treatment, and future directions. Circ Res. 2022;130(8):1204\u201329.","journal-title":"Circ Res"},{"issue":"3","key":"1867_CR13","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1161\/STROKEAHA.111.000411","volume":"44","author":"WA Mould","year":"2013","unstructured":"Mould WA, Carhuapoma JR, Muschelli J, et al. Minimally invasive surgery plus recombinant tissue-type plasminogen activator for intracerebral hemorrhage evacuation decreases perihematomal edema. Stroke. 2013;44(3):627\u201334.","journal-title":"Stroke"},{"issue":"Suppl_1","key":"1867_CR14","doi-asserted-by":"publisher","first-page":"A15","DOI":"10.1161\/str.50.suppl_1.15","volume":"50","author":"WA Mould","year":"2019","unstructured":"Mould WA, Muschelli J, Avadhani R, et al. Abstract 15: reduction in perihematomal edema leads to improved clinical outcomes: results from the MISTIE III trial. Stroke. 2019;50(Suppl_1):A15\u2013A15.","journal-title":"Stroke"},{"issue":"2","key":"1867_CR15","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1016\/j.bmcl.2006.10.028","volume":"17","author":"W Hu","year":"2007","unstructured":"Hu W, Ralay Ranaivo H, Roy SM, et al. Development of a novel therapeutic suppressor of brain proinflammatory cytokine up-regulation that attenuates synaptic dysfunction and behavioral deficits. Bioorg Med Chem Lett. 2007;17(2):414\u20138.","journal-title":"Bioorg Med Chem Lett"},{"key":"1867_CR16","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/S0074-7742(07)82015-0","volume":"82","author":"LJ Van Eldik","year":"2007","unstructured":"Van Eldik LJ, Thompson WL, Ralay Ranaivo H, Behanna HA, Martin WD. Glia proinflammatory cytokine upregulation as a therapeutic target for neurodegenerative diseases: function-based and target-based discovery approaches. Int Rev Neurobiol. 2007;82:277\u201396.","journal-title":"Int Rev Neurobiol"},{"issue":"6","key":"1867_CR17","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1097\/ALN.0b013e318253a02a","volume":"116","author":"ML James","year":"2012","unstructured":"James ML, Wang H, Cantillana V, et al. TT-301 inhibits microglial activation and improves outcome after central nervous system injury in adult mice. Anesthesiology. 2012;116(6):1299\u2013311.","journal-title":"Anesthesiology"},{"issue":"2","key":"1867_CR18","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1002\/cpdd.795","volume":"10","author":"LJ Van Eldik","year":"2021","unstructured":"Van Eldik LJ, Sawaki L, Bowen K, et al. First-in-human studies of MW01-6-189WH, a brain-penetrant, antineuroinflammatory small-molecule drug candidate: phase 1 safety, tolerability, pharmacokinetic, and pharmacodynamic studies in healthy adult volunteers. Clin Pharmacol Drug Dev. 2021;10(2):131\u201343.","journal-title":"Clin Pharmacol Drug Dev"},{"issue":"4","key":"1867_CR19","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1227\/NEU.0000000000001316","volume":"80","author":"MA Labib","year":"2017","unstructured":"Labib MA, Shah M, Kassam AB, et al. The safety and feasibility of image-guided brainpath-mediated transsulcul hematoma evacuation: a multicenter study. Neurosurgery. 2017;80(4):515\u201324.","journal-title":"Neurosurgery"},{"key":"1867_CR20","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1007\/978-3-211-09469-3_41","volume":"105","author":"T Morgan","year":"2008","unstructured":"Morgan T, Awad I, Keyl P, Lane K, Hanley D. Preliminary report of the clot lysis evaluating accelerated resolution of intraventricular hemorrhage (CLEAR-IVH) clinical trial. Acta Neurochir Suppl. 2008;105:217\u201320.","journal-title":"Acta Neurochir Suppl"},{"issue":"9","key":"1867_CR21","doi-asserted-by":"publisher","first-page":"2470","DOI":"10.1161\/STROKEAHA.114.007343","volume":"46","author":"AJS Webb","year":"2015","unstructured":"Webb AJS, Ullman NL, Morgan TC, et al. Accuracy of the ABC\/2 score for intracerebral hemorrhage: systematic review and analysis of MISTIE, CLEAR-IVH, and CLEAR III. Stroke. 2015;46(9):2470\u20136.","journal-title":"Stroke"},{"issue":"3","key":"1867_CR22","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1007\/s12021-020-09493-5","volume":"19","author":"MF Sharrock","year":"2021","unstructured":"Sharrock MF, Mould WA, Ali H, et al. 3D deep neural network segmentation of intracerebral hemorrhage: development and validation for clinical trials. Neuroinformatics. 2021;19(3):403\u201315.","journal-title":"Neuroinformatics"},{"issue":"4","key":"1867_CR23","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1007\/s12021-020-09462-y","volume":"18","author":"WL Nowinski","year":"2020","unstructured":"Nowinski WL. Human brain atlases in stroke management. Neuroinformatics. 2020;18(4):549\u201367.","journal-title":"Neuroinformatics"},{"issue":"Suppl 1","key":"1867_CR24","first-page":"A75","volume":"13","author":"B Jankowitz","year":"2021","unstructured":"Jankowitz B, Davies J, Schirmer C, et al. E-022: Viz RECRUIT ICH Volume increased the screening rate and enrollment in ENRICH. J Neurointerv Surg. 2021;13(Suppl 1):A75\u20136.","journal-title":"J Neurointerv Surg"},{"issue":"Suppl_1","key":"1867_CR25","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1161\/str.54.suppl_1.TMP44","volume":"54","author":"IC Odland","year":"2023","unstructured":"Odland IC, Schuldt BR, Liu K, et al. Abstract TMP44: artificial intelligence-driven automated intracerebral hemorrhage volume calculation is more accurate than ABC\/2. Stroke. 2023;54(Suppl_1):44.","journal-title":"Stroke"},{"issue":"7","key":"1867_CR26","doi-asserted-by":"publisher","first-page":"e282","DOI":"10.1161\/STR.0000000000000407","volume":"53","author":"SM Greenberg","year":"2022","unstructured":"Greenberg SM, Ziai WC, Cordonnier C, et al. 2022 guideline for the management of patients with spontaneous intracerebral hemorrhage: A Guideline from the American Heart Association\/American Stroke Association. Stroke. 2022;53(7):e282-361.","journal-title":"Stroke"},{"issue":"10175","key":"1867_CR27","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1016\/S0140-6736(19)30195-3","volume":"393","author":"DF Hanley","year":"2019","unstructured":"Hanley DF, Thompson RE, Rosenblum M, et al. Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial. Lancet. 2019;393(10175):1021\u201332.","journal-title":"Lancet"},{"issue":"11","key":"1867_CR28","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1056\/NEJMoa1603460","volume":"375","author":"AI Qureshi","year":"2016","unstructured":"Qureshi AI, Palesch YY, Barsan WG, et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. N Engl J Med. 2016;375(11):1033\u201343.","journal-title":"N Engl J Med"}],"container-title":["Neurocritical Care"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12028-023-01867-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12028-023-01867-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12028-023-01867-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,22]],"date-time":"2024-03-22T18:18:26Z","timestamp":1711131506000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12028-023-01867-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,2]]},"references-count":28,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2024,4]]}},"alternative-id":["1867"],"URL":"https:\/\/doi.org\/10.1007\/s12028-023-01867-2","relation":{},"ISSN":["1541-6933","1556-0961"],"issn-type":[{"value":"1541-6933","type":"print"},{"value":"1556-0961","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,2]]},"assertion":[{"value":"5 June 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 September 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 November 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Dr. Ziai reports grants from the National Institute on Aging and the National Institute of Neurological Disorders and Stroke; consulting fees from Lumosa Therapeutics and <i>Neurocritical Care<\/i>, for which she is an associate editor; meeting support from Integra; DSMB participation for C.R. Bard; and a leadership role in the Neurocritical Care Society as Neurocritical Care Research Central co-director. Dr. Thompson reports statistical consulting for Op2Lysis, a company testing a drug similar to MW189. Dr. Sansing reports grants from the National Institutes of Health and the American Heart Association. Dr. Van Eldik is an inventor on patents covering MW189 and a scientific founder of ImmunoChem Therapeutics LLC, a start-up formed to commercialize MW189. Her institution, University of Kentucky, might benefit if MW189 is successful commercially. Dr. Hanley reports grants from the National Institutes of Health and personal fees from Neurelis, Neurotrope, and medicolegal consulting.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The Johns Hopkins Medicine IRB, serving as the single IRB, approved the study design. The trial will be conducted in accordance with the principles of the Declaration of Helsinki, the Good Clinical Practice guidelines of the International Council for Harmonisation, and all applicable regulatory requirements. Written informed consent will be obtained from all participants or their legally authorized representatives.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical Approval\/Informed Consent"}},{"value":"ClinicalTrials.gov identifier NCT05020535.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Clinical Trial Registration"}}]}}