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
Pryor, Kent E
Coffey, Christopher S
Sawyer, Robert N
Rost, Natalia S
Froehler, Michael T
Clarke Haley, E
Mark Haacke, E
Davis, Thomas P
Toga, Arthur W
Griffin, John H
Zlokovic, Berislav V
AffiliationUniv Arizona, Coll Med, Dept Med Pharmacol
MetadataShow full item record
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.
JournalANNALS OF NEUROLOGY
Rights© 2018 American Neurological Association
Collection InformationThis 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 firstname.lastname@example.org.
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.
Note12 month embargo; first published: 18 November 2018
VersionFinal accepted manuscript
SponsorsNational 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]
- Selecting Patients for Intra-Arterial Therapy in the Context of a Clinical Trial for Neuroprotection.
- Authors: Lyden P, Weymer S, Coffey C, Cudkowicz M, Berg S, O'Brien S, Fisher M, Haley EC, Khatri P, Saver J, Levine S, Levy H, Rymer M, Wechsler L, Jadhav A, McNeil E, Waddy S, Pryor K
- Issue date: 2016 Dec
- Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers.
- Authors: Lyden P, Levy H, Weymer S, Pryor K, Kramer W, Griffin JH, Davis TP, Zlokovic B
- Issue date: 2013
- Activated protein C analog promotes neurogenesis and improves neurological outcome after focal ischemic stroke in mice via protease activated receptor 1.
- Authors: Wang Y, Zhao Z, Chow N, Ali T, Griffin JH, Zlokovic BV
- Issue date: 2013 Apr 24
- Activated protein C analog protects from ischemic stroke and extends the therapeutic window of tissue-type plasminogen activator in aged female mice and hypertensive rats.
- Authors: Wang Y, Zhao Z, Chow N, Rajput PS, Griffin JH, Lyden PD, Zlokovic BV
- Issue date: 2013 Dec
- Activated protein C, protease activated receptor 1, and neuroprotection.
- Authors: Griffin JH, Zlokovic BV, Mosnier LO
- Issue date: 2018 Jul 12