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

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.

Conflict of interest statement

POTENTIAL CONFLICTS OF INTEREST DISCLOSURES

KP is an employee of ZZ Biotech LLC. HL, TPD and JHG are consultants to ZZ Biotech, LLC. BVZ is scientific founder of ZZ Biotech LLC and chairs its Scientific Advisory Board. The remainder of the authors have no disclosures.

All data was collected independently of the corporate sponsor and stored at the University of Iowa, per Network of Excellence in Neuroscience Trials (NeuroNEXT) Standard Operating Procedures. All analyses were approved by the PI and the senior biostatistician. Although company representatives were present on team phone calls, the investigators retained full control over data, event adjudication, analyses, interpretation and drafting of the manuscript.

© 2018 American Neurological Association.

Figures

Figure One:

Image Analysis Method for Hemorrhage Volume Quantification. The analyst (unaware of treatment assignment) identified the infarct region using FLAIR (A), then reviewed the susceptibility sequence (B). An object was drawn around abnormal findings (C), and a threshold was applied within the object to outline any hemorrhage (D). The number of pixels lower than the threshold was produced through SPIN software and converted to areas (Spintech Inc., Bingham Farms MI, USA).

Figure Two:

CONSORT Diagram Showing Patients Screened and Then Ultimately Enrolled. Due to the time-compressed nature of acute stroke clinical trials, we screened 2814 patients, obtained consent from 130 patients, and we enrolled 110 patients into the protocol. Of the 20 consented/not-enrolled patients, 1 patient was found to be ineligible prior to first dose, 7 became clinically unstable, 7 did not receive drug before expiration of the enrollment window, and 5 cleared symptoms to NIHSS