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Mitchell W. Krucoff, C.K. Ponde, Jagdish Hiremath, Mullasari Ajit,

A Prospective Randomized Trial of CMX-2043, a Lipoic Acid-Based Cytoprotectant , In Patients Undergoing Elective PCI: Primary Results of the SUPPORT-1 Trial. Mitchell W. Krucoff, C.K. Ponde, Jagdish Hiremath, Mullasari Ajit, Eddison Ramsaran, Manesh R. Patel, Alan S. Lader,

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Mitchell W. Krucoff, C.K. Ponde, Jagdish Hiremath, Mullasari Ajit,

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  1. A Prospective Randomized Trial of CMX-2043, a Lipoic Acid-Based Cytoprotectant, In Patients Undergoing Elective PCI: Primary Results of the SUPPORT-1 Trial Mitchell W. Krucoff, C.K. Ponde, Jagdish Hiremath, Mullasari Ajit, Eddison Ramsaran, Manesh R. Patel, Alan S. Lader, F. Howard Schneider, Reinier Beeuwkes, C. Michael Gibson, and James E. Tcheng.

  2. Conflict of Interest Clinical Advisory Board, Ischemix

  3. Resolute All Comers 2,121 patients Incidence & Implications of Peri-Procedural MI:A Controversy of Definitions & Pathophysiology Incidence: 3.6-17.8% 3 yr mortality: 2-8%

  4. PCI produces enzymatic events Selected protein elevations (CPK-MB, Troponin) represent myocellular necrosis PCI as a laboratory for RCT of cytoprotective strategies has FDA predicate (vitamin B6 metabolite pyridoxal-5’-phosphate monohydrate (MC-1) in the MC-1 to Eliminate Necrosis and Damage (MEND-1) PCI: A Human Laboratory for Cytoprotection

  5. CMS-2043: A Novel Molecular Entity to Inhibit Ischemic Apoptosis • Reactive oxygen species (ROS) anti-oxidant, AND • Activates Akt(Ak mouse thymoma = Protein kinase B) via tyrosine kinase (TK)

  6. Safety and Efficacy of CMX-2043 in Subjects Undergoing PCI and Peri-Operative Reperfusion Treatment The SUPPORT 1 Study

  7. SUPPORT-1: Study Design Phase IIa Safety & Efficacy: CMX-2043 Prospective, randomized 3:1 3 doses (0.8, 1.6 & 2.4 mg/kg) vs placebo Multi-center (N=6) Elective PCI Patients WNL biomarkers & Non-acute ECG Receiving single stent of ≥ 18 mm or multiple stents Primary Outcome Measures: Incidence of CK-MB elevation <24 hours following PCI Change in cardiac biomarkers <24 hrs following PCI CK-MB, Troponin T Secondary Outcome Measure: MI as >X3 peak CPK

  8. SUPPORT-1 Exclusion Criteria Acute/unstable angina MI within 14 days Coagulopathy Clinical valvular disease Clinical peripheral vascular disease TIA, stroke or IC bleed within 90 days Creatinine level ≥ 1.5 times ULN

  9. SUPPORT-1 Sites and Investigators

  10. SUPPORT I: Patient Accrual/Randomization Total patients enrolled N=142 Placebo N= 35 0.8 mg/Kg N= 36 1.6 mg/Kg N= 35 2.4 mg/Kg N= 36 0.8 mg/Kg (100%) 1.6 mg/Kg (97.1 %) 2.4 mg/Kg (100%) Placebo (100%) 1 subject withdrawn

  11. SUPPORT-1 Baseline Characteristics

  12. SUPPORT I: Arteries Stented Per Rx Group

  13. Primary Endpoint:24 Hr CK-MB Change from Baseline

  14. 24 Hr CK-MB Change From Baseline (ng/mL) p = 0.05 p=0.05 vs. Placebo CMX-2043 treatment

  15. 24 Hr Troponin T Change from Baseline CMX-2043 treatment

  16. 24 Hr Peri-Procedural MI by CK-MB >X3 ULN p=0.024 vs. Placebo CMX-2043 treatment

  17. 24 Hr Peri-Procedural MI by Troponin T >X3 ULN p=0.050 vs. Placebo CMX-2043 treatment

  18. SUPPORT-1 Adverse Events Summary

  19. SUPPORT I: Limitations • Serum marker elevations with elective PCI have biochemical relevance for NME testing vs. human apoptosis, however the clinical relevance of these findings is unproven

  20. SUPPORT I was a prospective, randomized, multicenter Phase IIa dosing study of protection from PCI-induced myonecrosis by CMX-2043 infusion All doses of CMX-2043 studied (0.8, 1.6 and 2.4 mg/kg) appeared safe in this population High dose (2.4 mg/kg) infusion of CMX-2043 was associated with statistically significant reduction of serum markers of myonecrosis and MI defined by >3X elevation above ULN Results of SUPPORT I suggest the basis for further study and a Phase III study design SUPPORT I Primary Results: Conclusions

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