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
| Autor: | Julie Qidwai, E. Mark Haacke, Michael T. Froehler, Jan Claassen, Curtis G. Benesch, Arthur W. Toga, Ashutosh P Jadhav, Howard P. Levy, Shlee S. Song, Kim Magee, Robert N. Sawyer, Marilyn M Rymer, Michael A. Rippee, Archana Hinduja, Thomas P. Davis, Mark Johnson, Merit Cudkowicz, Michel T. Torbey, Miller Fawaz, Kent E. Pryor, Peter M Hannon, Patrick D. Lyden, Opeolu Adeoye, Berislav V. Zlokovic, E. Clarke Haley, Jon W. Yankey, Robin Conwit, John H. Griffin, Jin-Moo Lee, Natalia S. Rost, Christopher S. Coffey |
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| Rok vydání: | 2019 |
| Předmět: |
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0301 basic medicine medicine.medical_treatment Population Placebo Severity of Illness Index Tissue plasminogen activator Article Brain Ischemia law.invention 03 medical and health sciences 0302 clinical medicine Randomized controlled trial law medicine Humans Single-Blind Method education Stroke Aged Thrombectomy Aged 80 and over education.field_of_study business.industry Thrombolysis Middle Aged medicine.disease Combined Modality Therapy Recombinant Proteins Clinical trial 030104 developmental biology Neurology Tolerability Tissue Plasminogen Activator Anesthesia Drug Therapy Combination Female Neurology (clinical) business 030217 neurology & neurosurgery Protein C medicine.drug |
| Zdroj: | Annals of Neurology. 85:125-136 |
| ISSN: | 0364-5134 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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