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

• Published in: Annals of neurology Vol. 85; no. 1; pp. 125 - 136
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-01-2019; Wiley Subscription Services, Inc
• Subjects: Activated protein C; Aged; Aged, 80 and over; Brain Ischemia - diagnostic imaging; Brain Ischemia - drug therapy; Brain Ischemia - surgery; Clinical trials; Combined Modality Therapy - methods; Combined treatment; Demographics; Demography; Dosage; Drug Therapy, Combination; Female; Hemorrhage; Human performance; Humans; Injury prevention; Intravenous administration; Ischemia; Male; Middle Aged; Neuroprotective agents; Patients; Protein C - administration & dosage; Proteins; Randomization; Recombinant Proteins - administration & dosage; Severity of Illness Index; Single-Blind Method; Stroke; Stroke - diagnostic imaging; Stroke - drug therapy; Stroke - surgery; t-Plasminogen activator; Thrombectomy - methods; Thrombolysis; Tissue Plasminogen Activator - administration & dosage; Tissues; Toxicity
• ISSN: 0364-5134; 1531-8249; 1531-8249
• DOI: 10.1002/ana.25383

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.