Michael L James1,2,3, Jesse Troy4, Nathaniel Nowacki5, Jordan Komisarow6, Christa B Swisher7, Kristi Tucker8, Kevin Hatton9, Marc A Babi10, Bradford B Worrall11, Charles Andrews12, Daniel Woo13, Peter G Kranz14, Christopher Lascola14, Maureen Maughan15, Daniel T Laskowitz16,7,17,15. 1. Department of Anesthesiology, Duke University, Durham, NC, USA. michael.james@duke.edu. 2. Department of Neurology, Duke University, Durham, NC, USA. michael.james@duke.edu. 3. Duke Clinical Research Institute, Duke University, Durham, NC, USA. michael.james@duke.edu. 4. Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA. 5. Hospital Care, Hattiesburg Clinic Neurology, Hattiesburg, MS, USA. 6. Department of Neurosurgery, Duke University, Durham, NC, USA. 7. Department of Neurology, Duke University, Durham, NC, USA. 8. Department of Neurology, Wake Forest-Baptist Health, Winston-Salem, NC, USA. 9. Department of Anesthesiology, University of Kentucky, Lexington, KY, USA. 10. Departments of Neurology and Neurosurgery, University of Florida, Gainesville, FL, USA. 11. Departments of Neurology and Public Health Sciences, University of Virginia, Charlottesvile, VA, USA. 12. Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA. 13. Department of Neurology, University of Cincinnati, Cincinnati, OH, USA. 14. Department of Radiology, Duke University, Durham, NC, USA. 15. AegisCN, LLC, Durham, NC, USA. 16. Department of Anesthesiology, Duke University, Durham, NC, USA. 17. Duke Clinical Research Institute, Duke University, Durham, NC, USA.
Abstract
BACKGROUND: Endogenous apolipoprotein (apo) E mediates neuroinflammatory responses and recovery after brain injury. Exogenously administered apoE-mimetic peptides effectively penetrate the central nervous system compartment and downregulate acute inflammation. CN-105 is a novel apoE-mimetic pentapeptide with excellent evidence of functional and histological improvement in preclinical models of intracerebral hemorrhage (ICH). The CN-105 in participants with Acute supraTentorial intraCerebral Hemorrhage (CATCH) trial is a first-in-disease-state multicenter open-label trial evaluating safety and feasability of CN-105 administration in patients with acute primary supratentorial ICH. METHODS: Eligible patients were aged 30-80 years, had confirmed primary supratentorial ICH, and were able to intiate CN-105 administration (1.0 mg/kg every 6 h for 72 h) within 12 h of symptom onset. A priori defined safety end points, including hematoma volume, pharmacokinetics, and 30-day neurological outcomes, were analyzed. For clinical outcomes, CATCH participants were compared 1:1 with a closely matched contemporary ICH cohort through random selection. Hematoma volumes determined from computed tomography images on days 0, 1, 2, and 5 and ordinal modified Rankin Scale score at 30 days after ICH were compared. RESULTS: In 38 participants enrolled across six study sites in the United States, adverse events occurred at an expected rate without increase in hematoma expansion or neurological deterioration. CN-105 treatment had an odds ratio (95% confidence interval) of 2.69 (1.31-5.51) for lower 30-day modified Rankin Scale score, after adjustment for ICH score, sex, and race/ethnicity, as compared with a matched contemporary cohort. CONCLUSIONS: CN-105 administration represents an excellent translational candidate for treatment of acute ICH because of its safety, dosing feasibility, favorable pharmacokinetics, and possible improvement in neurological recovery.
BACKGROUND: Endogenous apolipoprotein (apo) E mediates neuroinflammatory responses and recovery after brain injury. Exogenously administered apoE-mimetic peptides effectively penetrate the central nervous system compartment and downregulate acute inflammation. CN-105 is a novel apoE-mimetic pentapeptide with excellent evidence of functional and histological improvement in preclinical models of intracerebral hemorrhage (ICH). The CN-105 in participants with Acute supraTentorial intraCerebral Hemorrhage (CATCH) trial is a first-in-disease-state multicenter open-label trial evaluating safety and feasability of CN-105 administration in patients with acute primary supratentorial ICH. METHODS: Eligible patients were aged 30-80 years, had confirmed primary supratentorial ICH, and were able to intiate CN-105 administration (1.0 mg/kg every 6 h for 72 h) within 12 h of symptom onset. A priori defined safety end points, including hematoma volume, pharmacokinetics, and 30-day neurological outcomes, were analyzed. For clinical outcomes, CATCH participants were compared 1:1 with a closely matched contemporary ICH cohort through random selection. Hematoma volumes determined from computed tomography images on days 0, 1, 2, and 5 and ordinal modified Rankin Scale score at 30 days after ICH were compared. RESULTS: In 38 participants enrolled across six study sites in the United States, adverse events occurred at an expected rate without increase in hematoma expansion or neurological deterioration. CN-105 treatment had an odds ratio (95% confidence interval) of 2.69 (1.31-5.51) for lower 30-day modified Rankin Scale score, after adjustment for ICH score, sex, and race/ethnicity, as compared with a matched contemporary cohort. CONCLUSIONS: CN-105 administration represents an excellent translational candidate for treatment of acute ICH because of its safety, dosing feasibility, favorable pharmacokinetics, and possible improvement in neurological recovery.
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