Journal article
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, Vol.85(1), pp.125-136
01/2019
DOI: 10.1002/ana.25383
PMCID: PMC6342508
PMID: 30450637
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.
Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714. ANN NEUROL 2019;85:125-136.
Details
- Title: Subtitle
- 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
- Creators
- Patrick Lyden - Cedars-Sinai Medical Center, Los Angeles, CAKent E Pryor - ZZ Biotech, LLC, Houston, TXChristopher S Coffey - The University of Iowa, Iowa City, IAMerit Cudkowicz - Massachusetts General Hospital, Neurological Clinical Research Institute, Boston, MARobin Conwit - National Institutes of Health, National Institute of Neurological Disorders and Stroke, Bethesda, MDAshutosh Jadhav - University of Pittsburgh Medical School, Pittsburgh, PARobert N Sawyer Jr - State University of New York-University at Buffalo, Buffalo, NYJan Claassen - Neurological Institute, Columbia University, New York, NYOpeolu Adeoye - Department of Emergency Medicine, University of Cincinnati, Cincinnati, OHShlee Song - Cedars-Sinai Medical Center, Los Angeles, CAPeter Hannon - University of Utah, Salt Lake City, UTNatalia S Rost - Massachusetts General Hospital, Neurological Clinical Research Institute, Boston, MAArchana Hinduja - Ohio State University Medical Center, Columbus, OHMichel Torbey - Ohio State University Medical Center, Columbus, OHJin-Moo Lee - Barnes-Jewish Hospital, St. Louis, MOCurtis Benesch - University of Rochester Medical Center, Rochester, NYMichael Rippee - The University of Kansas Hospital, Kansas City, KSMarilyn Rymer - The University of Kansas Hospital, Kansas City, KSMichael T Froehler - Cerebrovascular Program, Vanderbilt University Medical Center, Nashville, TNE Clarke Haley - University of Virginia, Charlottesville, VAMark Johnson - Southwestern Medical Center, University of Texas, Dallas, TXJon Yankey - The University of Iowa, Iowa City, IAKim Magee - The University of Iowa, Iowa City, IAJulie Qidwai - The University of Iowa, Iowa City, IAHoward Levy - Consultant, ZZ Biotech, LLCE Mark Haacke - The MRI Institute for Biomedical Research, Bingham Farms, MIMiller Fawaz - The MRI Institute for Biomedical Research, Bingham Farms, MIThomas P Davis - Department of Medical Pharmacology, College of Medicine, University of Arizona, Tucson, AZArthur W Toga - Laboratory of Neuro Imaging, Institute of Neuroimaging and Informatics, Keck School of Medicine, University of Southern California Los Angeles, Los Angeles, CAJohn H Griffin - The Scripps Research Institute, La Jolla, CABerislav V Zlokovic - Zilkha Neurogenetic Institute and Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California Los Angeles, Los Angeles, CANeuroNEXT Clinical Trials Network NN104 Investigators
- Resource Type
- Journal article
- Publication Details
- Annals of neurology, Vol.85(1), pp.125-136
- DOI
- 10.1002/ana.25383
- PMID
- 30450637
- PMCID
- PMC6342508
- ISSN
- 0364-5134
- eISSN
- 1531-8249
- Grant note
- U24 NS107165 / NINDS NIH HHS U10 NS077265 / NINDS NIH HHS U01 NS077352 / NINDS NIH HHS R01 NS075930 / NINDS NIH HHS UL1 TR001412 / NCATS NIH HHS U01 NS077179 / NINDS NIH HHS P01 AG052350 / NIA NIH HHS UL1 TR000040 / NCATS NIH HHS UL1 TR002345 / NCATS NIH HHS U24 NS107128 / NINDS NIH HHS UL1 TR000448 / NCATS NIH HHS U01 NS088312 / NINDS NIH HHS
- Language
- English
- Date published
- 01/2019
- Academic Unit
- Biostatistics
- Record Identifier
- 9984214703002771
Metrics
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