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Ann Neurol. 2019 Jan;85(1):125-136. doi: 10.1002/ana.25383. Epub 2019 Jan 7.

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.

Author information

1
Cedars-Sinai Medical Center, Los Angeles, CA.
2
ZZ Biotech, LLC, Houston, TX.
3
The University of Iowa, Iowa City, IA.
4
Massachusetts General Hospital, Neurological Clinical Research Institute, Boston, MA.
5
National Institutes of Health, National Institute of Neurological Disorders and Stroke, Bethesda, MD.
6
University of Pittsburgh Medical School, Pittsburgh, PA.
7
State University of New York-University at Buffalo, Buffalo, NY.
8
Neurological Institute, Columbia University, New York, NY.
9
Department of Emergency Medicine, University of Cincinnati, Cincinnati, OH.
10
University of Utah, Salt Lake City, UT.
11
Ohio State University Medical Center, Columbus, OH.
12
Barnes-Jewish Hospital, St. Louis, MO.
13
University of Rochester Medical Center, Rochester, NY.
14
The University of Kansas Hospital, Kansas City, KS.
15
Cerebrovascular Program, Vanderbilt University Medical Center, Nashville, TN.
16
University of Virginia, Charlottesville, VA.
17
Southwestern Medical Center, University of Texas, Dallas, TX.
18
Consultant, ZZ Biotech, LLC.
19
The MRI Institute for Biomedical Research, Bingham Farms, MI.
20
Department of Medical Pharmacology, College of Medicine, University of Arizona, Tucson, AZ.
21
Laboratory of Neuro Imaging, Institute of Neuroimaging and Informatics, Keck School of Medicine, University of Southern California Los Angeles, Los Angeles, CA.
22
The Scripps Research Institute, La Jolla, CA.
23
Zilkha Neurogenetic Institute and Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California Los Angeles, Los Angeles, CA.

Abstract

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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).

INTERPRETATION:

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:

Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714. ANN NEUROL 2019;85:125-136.

PMID:
30450637
PMCID:
PMC6342508
[Available on 2020-01-07]
DOI:
10.1002/ana.25383

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