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    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

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    ana.25383.pdf
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    Final Accepted Manuscript
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    Author
    Lyden, Patrick
    Pryor, Kent E
    Coffey, Christopher S
    Cudkowicz, Merit
    Conwit, Robin
    Jadhav, Ashutosh
    Sawyer, Robert N
    Claassen, Jan
    Adeoye, Opeolu
    Song, Shlee
    Hannon, Peter
    Rost, Natalia S
    Hinduja, Archana
    Torbey, Michel
    Lee, Jin-Moo
    Benesch, Curtis
    Rippee, Michael
    Rymer, Marilyn
    Froehler, Michael T
    Clarke Haley, E
    Johnson, Mark
    Yankey, Jon
    Magee, Kim
    Qidwai, Julie
    Levy, Howard
    Mark Haacke, E
    Fawaz, Miller
    Davis, Thomas P
    Toga, Arthur W
    Griffin, John H
    Zlokovic, Berislav V
    Show allShow less
    Affiliation
    Univ Arizona, Coll Med, Dept Med Pharmacol
    Issue Date
    2019-01-01
    
    Metadata
    Show full item record
    Publisher
    WILEY
    Citation
    Lyden, 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.
    Journal
    ANNALS OF NEUROLOGY
    Rights
    © 2018 American Neurological Association
    Collection Information
    This 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.
    Abstract
    Agonism 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.
    Note
    12 month embargo; first published: 18 November 2018
    ISSN
    1531-8249
    PubMed ID
    30450637
    DOI
    10.1002/ana.25383
    Version
    Final accepted manuscript
    Sponsors
    National 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]
    ae974a485f413a2113503eed53cd6c53
    10.1002/ana.25383
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