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dc.contributor.authorLyden, Patrick
dc.contributor.authorPryor, Kent E
dc.contributor.authorCoffey, Christopher S
dc.contributor.authorCudkowicz, Merit
dc.contributor.authorConwit, Robin
dc.contributor.authorJadhav, Ashutosh
dc.contributor.authorSawyer, Robert N
dc.contributor.authorClaassen, Jan
dc.contributor.authorAdeoye, Opeolu
dc.contributor.authorSong, Shlee
dc.contributor.authorHannon, Peter
dc.contributor.authorRost, Natalia S
dc.contributor.authorHinduja, Archana
dc.contributor.authorTorbey, Michel
dc.contributor.authorLee, Jin-Moo
dc.contributor.authorBenesch, Curtis
dc.contributor.authorRippee, Michael
dc.contributor.authorRymer, Marilyn
dc.contributor.authorFroehler, Michael T
dc.contributor.authorClarke Haley, E
dc.contributor.authorJohnson, Mark
dc.contributor.authorYankey, Jon
dc.contributor.authorMagee, Kim
dc.contributor.authorQidwai, Julie
dc.contributor.authorLevy, Howard
dc.contributor.authorMark Haacke, E
dc.contributor.authorFawaz, Miller
dc.contributor.authorDavis, Thomas P
dc.contributor.authorToga, Arthur W
dc.contributor.authorGriffin, John H
dc.contributor.authorZlokovic, Berislav V
dc.date.accessioned2019-03-11T20:01:40Z
dc.date.available2019-03-11T20:01:40Z
dc.date.issued2019-01-01
dc.identifier.citationLyden, P., Pryor, K. E., Coffey, C. S., Cudkowicz, M., Conwit, R., Jadhav, A., ... & Hannon, P. (2018). Final Results of the RHAPSODY trial: A multi‐center, Phase 2 trial using a continual reassessment method to determine the safety and tolerability of 3K3A‐APC, a Recombinant Variant of Human Activated Protein C, in combination with tissue plasminogen activator, mechanical thrombectomy or both in moderate to severe acute ischemic stroke. Annals of neurology.en_US
dc.identifier.issn1531-8249
dc.identifier.pmid30450637
dc.identifier.doi10.1002/ana.25383
dc.identifier.urihttp://hdl.handle.net/10150/631825
dc.description.abstractAgonism of protease-activated receptor (PAR) 1 by activated protein C (APC) provides neuro- and vasculoprotection in experimental neuroinjury models. The pleiotropic PAR1 agonist, 3K3A-APC, reduces neurological injury and promotes vascular integrity; 3K3A-APC proved safe in human volunteers. We performed a randomized, controlled, blinded trial to determine the maximally tolerated dose (MTD) of 3K3A-APC in ischemic stroke patients. The NeuroNEXT trial, RHAPSODY, used a novel continual reassessment method to determine the MTD using tiers of 120, 240, 360, and 540 μg/kg of 3K3A-APC. After intravenous tissue plasminogen activator, intra-arterial mechanical thrombectomy, or both, patients were randomized to 1 of the 4 doses or placebo. Vasculoprotection was assessed as microbleed and intracranial hemorrhage (ICH) rates. Between January 2015 and July 2017, we treated 110 patients. Demographics resembled a typical stroke population. The MTD was the highest-dose 3K3A-APC tested, 540 μg/kg, with an estimated toxicity rate of 7%. There was no difference in prespecified ICH rates. In exploratory analyses, 3K3A-APC reduced ICH rates compared to placebo from 86.5% to 67.4% in the combined treatment arms (p = 0.046) and total hemorrhage volume from an average of 2.1 ± 5.8 ml in placebo to 0.8 ± 2.1 ml in the combined treatment arms (p = 0.066). RHAPSODY is the first trial of a neuroprotectant for acute ischemic stroke in a trial design allowing thrombectomy, thrombolysis, or both. The MTD was 540 μg/kg for the PAR1 active cytoprotectant, 3K3A-APC. A trend toward lower hemorrhage rate in an exploratory analysis requires confirmation.en_US
dc.description.sponsorshipNational Institute of Neurological Disorders and Stroke (NINDS) [U01NS088312]; National Institute of Neurological Disorders and Stroke [U01NS077179, U01NS077352]; Vanderbilt University [ULTR002243]; Washington University at St. Louis [UL1TR000448]; Columbia University Medical Center [UL1TR000040]; University at Buffalo/SUNY [UL1TR001412]en_US
dc.language.isoenen_US
dc.publisherWILEYen_US
dc.rights© 2018 American Neurological Associationen_US
dc.titleFinal Results of the RHAPSODY Trial: A Multi-Center, Phase 2 Trial Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC, A Recombinant Variant of Human Activated Protein C, in Combination with Tissue Plasminogen Activator, Mechanical Thrombectomy or both in Moderate to Severe Acute Ischemic Strokeen_US
dc.typeArticleen_US
dc.contributor.departmentUniv Arizona, Coll Med, Dept Med Pharmacolen_US
dc.identifier.journalANNALS OF NEUROLOGYen_US
dc.description.note12 month embargo; first published: 18 November 2018en_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal accepted manuscripten_US
dc.source.journaltitleAnnals of neurology


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