Trial reportAnnals of neurology2019
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.
Trial report in Annals of neurology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. It is linked to trial NCT02222714 (A Multi-center, Phase 2 Study Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC in Combination With tPA, Mechanical Thrombectomy or Both in Moderate to Severe Acute Ischemic Stroke), which is not on this map. Cited by 92 papers, 4 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Multi-center, Phase 2 Study Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC in Combination With tPA, Mechanical Thrombectomy or Both in Moderate to Severe Acute Ischemic Stroke
Who cites it
92 citing papers in PubMed, 4 syntheses or guidelines pooled it, 142 citations in OpenAlex.
- Asymptomatic Intracerebral Hemorrhage Following Endovascular Stroke Therapy Is Not Benign: A Systematic Review and Meta-Analysis.Journal of the American Heart Association · 2024Pooled it
- Common Pathways of Epileptogenesis in Patients With Epilepsy Post-Brain Injury: Findings From a Systematic Review and Meta-analysis.Neurology · 2023Pooled it
- Pooled it
- Systematic Review - Combining Neuroprotection With Reperfusion in Acute Ischemic Stroke.Frontiers in neurology · 2022Pooled it
- Safety and Efficacy of Otaplimastat in Patients with Acute Ischemic Stroke Requiring tPA (SAFE-TPA): A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2 Study.Annals of neurology · 2020Trial
- Dengzhanxixin injection for acute ischemic stroke after reperfusion therapy: A double-blind, placebo-controlled, multi-center clinical trial.IBRO neuroscience reports · 2026Article
- Beyond Recanalization: Neurovascular Unit Protection and Precision Adjunctive Therapy for Ischemic Stroke in the Reperfusion Era.Biomolecules · 2026Review
- Cell-to-Cell Signaling Networks at the Blood-Brain Barrier in Health and Disease.Arteriosclerosis, thrombosis, and vascular biology · 2026Review
- Microbiota, systemic immunity, and extracellular vesicles in stroke: peripheral nodes as therapeutic leverage points.Journal of neuroinflammation · 2026Review
- Cytoprotection Concepts for Ischemic Stroke in the Recanalization Era.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Activated Protein C and the Retina: From Physiology to Therapeutic Potential.International journal of molecular sciences · 2026Review
- Microcirculatory failure after successful recanalization in ischemic stroke: insights into mechanisms, imaging, and therapeutic strategies.Frontiers in pharmacology · 2026Review
- Protease-Activated Receptors (PARs): Biology and Therapeutic Potential in Perioperative Stroke.Translational stroke research · 2025Review
- On Inclusion of Covariates in Model Based Dose Finding Clinical Trial Designs.Statistics in medicine · 2025Article
- Complement inhibition targets a rich-club within the neuroinflammatory network after stroke to improve radiographic and functional outcomes.Journal of neuroinflammation · 2025Article
- Before, during, and after: An Argument for Safety and Improved Outcome of Thrombolysis in Acute Ischemic Stroke with Direct Oral Anticoagulant Treatment.Annals of neurology · 2024Review
- Reperfusion and cytoprotective agents are a mutually beneficial pair in ischaemic stroke therapy: an overview of pathophysiology, pharmacological targets and candidate drugs focusing on excitotoxicity and free radical.Stroke and vascular neurology · 2024Review
- Safety and tolerability of the protein C activator AB002 in end-stage renal disease patients on hemodialysis: a randomized phase 2 trial.Communications medicine · 2024Article
- Comprehensive Management of Stroke: From Mechanisms to Therapeutic Approaches.International journal of molecular sciences · 2024Review
- A promising frontier: targeting NETs for stroke treatment breakthroughs.Cell communication and signaling : CCS · 2024Review
32 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
32 authors at 20 institutions in 2 countries.
Funding
Abstract
objectiveAgonism 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.
methodsThe 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.
resultsBetween 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).
interpretationRHAPSODY 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 registrationClinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714. ANN NEUROL 2019;85:125-136.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.