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 Activ Academic Article uri icon

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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.

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
  • Haacke, Mark
  • Fawaz, Miller
  • Davis, Thomas P
  • Toga, Arthur W
  • Griffin, John H
  • Zlokovic, Berislav V

publication date

  • January 2019