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 the protease activated receptor (PAR) 1 by activated protein C (APC) provides neuroprotection and vasculoprotection in experimental neuro‐injury models. The pleiotropic PAR1 agonist, 3K3A‐APC, reduces neurologic 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 540μg/kg 3K3A‐APC. After intravenous tissue plasminogen activator, intraarterial mechanical thrombectomy, or both, patients were randomized to one of the four 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, 540μg/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 540μg/kg for the PAR1 active cytoprotectant 3K3A‐APC. A trend toward lower hemorrhage rate in an exploratory analysis requires confirmation.

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