PAR1 (Protease-Activated Receptor 1) Pepducin Therapy Targeting Myocardial Necrosis in Coronary Artery Disease and Acute Coronary Syndrome Patients Undergoing Cardiac Catheterization : A Randomized, Placebo-Controlled, Phase 2 Study
OBJECTIVE: Arterial thrombosis leading to ischemic injury worsens the prognosis of many patients with cardiovascular disease. PZ-128 is a first-in-class pepducin that reversibly inhibits PAR1 (protease-activated receptor 1) on platelets and other vascular cells by targeting the intracellular surface of the receptor. The TRIP-PCI (Thrombin Receptor Inhibitory Pepducin in Percutaneous Coronary Intervention) trial was conducted to assess the safety and efficacy of PZ-128 in patients undergoing cardiac catheterization with intent to perform percutaneous coronary intervention. Approach and Results: In this randomized, double-blind, placebo-controlled, phase 2 trial, 100 patients were randomly assigned (2:1) to receive PZ-128 (0.3 or 0.5 mg/kg), or placebo in a 2-hour infusion initiated just before the start of cardiac catheterization, on top of standard oral antiplatelet therapy. Rates of the primary end point of bleeding were not different between the combined PZ-128 doses (1.6%, 1/62) and placebo group (0%, 0/35). The secondary end points of major adverse coronary events at 30 and 90 days did not significantly differ but were numerically lower in the PZ-128 groups (0% and 2% in the PZ-128 groups, 6% and 6% with placebo, p=0.13, p=0.29, respectively). In the subgroup of patients with elevated baseline cardiac troponin I, the exploratory end point of 30-day major adverse coronary events + myocardial injury showed 83% events in the placebo group versus 31% events in the combined PZ-128 drug groups, an adjusted relative risk of 0.14 (95% CI, 0.02-0.75); P=0.02.
CONCLUSIONS: In this first-in-patient experience, PZ-128 added to standard antiplatelet therapy appeared to be safe, well tolerated, and potentially reduced periprocedural myonecrosis, thus providing the basis for further clinical trials. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02561000.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:40 |
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| Enthalten in: |
Arteriosclerosis, thrombosis, and vascular biology - 40(2020), 12 vom: 10. Dez., Seite 2990-3003 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Kuliopulos, Athan [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.12.2020 Date Revised 14.12.2020 published: Print-Electronic ClinicalTrials.gov: NCT02561000 Citation Status MEDLINE |
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| doi: |
10.1161/ATVBAHA.120.315168 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM315982101 |
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| 100 | 1 | |a Kuliopulos, Athan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a PAR1 (Protease-Activated Receptor 1) Pepducin Therapy Targeting Myocardial Necrosis in Coronary Artery Disease and Acute Coronary Syndrome Patients Undergoing Cardiac Catheterization |b A Randomized, Placebo-Controlled, Phase 2 Study |
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| 500 | |a Date Completed 14.12.2020 | ||
| 500 | |a Date Revised 14.12.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT02561000 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a OBJECTIVE: Arterial thrombosis leading to ischemic injury worsens the prognosis of many patients with cardiovascular disease. PZ-128 is a first-in-class pepducin that reversibly inhibits PAR1 (protease-activated receptor 1) on platelets and other vascular cells by targeting the intracellular surface of the receptor. The TRIP-PCI (Thrombin Receptor Inhibitory Pepducin in Percutaneous Coronary Intervention) trial was conducted to assess the safety and efficacy of PZ-128 in patients undergoing cardiac catheterization with intent to perform percutaneous coronary intervention. Approach and Results: In this randomized, double-blind, placebo-controlled, phase 2 trial, 100 patients were randomly assigned (2:1) to receive PZ-128 (0.3 or 0.5 mg/kg), or placebo in a 2-hour infusion initiated just before the start of cardiac catheterization, on top of standard oral antiplatelet therapy. Rates of the primary end point of bleeding were not different between the combined PZ-128 doses (1.6%, 1/62) and placebo group (0%, 0/35). The secondary end points of major adverse coronary events at 30 and 90 days did not significantly differ but were numerically lower in the PZ-128 groups (0% and 2% in the PZ-128 groups, 6% and 6% with placebo, p=0.13, p=0.29, respectively). In the subgroup of patients with elevated baseline cardiac troponin I, the exploratory end point of 30-day major adverse coronary events + myocardial injury showed 83% events in the placebo group versus 31% events in the combined PZ-128 drug groups, an adjusted relative risk of 0.14 (95% CI, 0.02-0.75); P=0.02 | ||
| 520 | |a CONCLUSIONS: In this first-in-patient experience, PZ-128 added to standard antiplatelet therapy appeared to be safe, well tolerated, and potentially reduced periprocedural myonecrosis, thus providing the basis for further clinical trials. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02561000 | ||
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Multicenter Study | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a acute coronary syndrome | |
| 650 | 4 | |a coronary artery disease | |
| 650 | 4 | |a myocardial infarction | |
| 650 | 4 | |a percutaneous coronary intervention | |
| 650 | 4 | |a troponin | |
| 650 | 7 | |a Cell-Penetrating Peptides |2 NLM | |
| 650 | 7 | |a Lipopeptides |2 NLM | |
| 650 | 7 | |a PZ-128 peptide |2 NLM | |
| 650 | 7 | |a Platelet Aggregation Inhibitors |2 NLM | |
| 650 | 7 | |a Receptor, PAR-1 |2 NLM | |
| 700 | 1 | |a Gurbel, Paul A |e verfasserin |4 aut | |
| 700 | 1 | |a Rade, Jeffrey J |e verfasserin |4 aut | |
| 700 | 1 | |a Kimmelstiel, Carey D |e verfasserin |4 aut | |
| 700 | 1 | |a Turner, Susan E |e verfasserin |4 aut | |
| 700 | 1 | |a Bliden, Kevin P |e verfasserin |4 aut | |
| 700 | 1 | |a Fletcher, Elizabeth K |e verfasserin |4 aut | |
| 700 | 1 | |a Cox, Daniel H |e verfasserin |4 aut | |
| 700 | 1 | |a Covic, Lidija |e verfasserin |4 aut | |
| 700 | 0 | |a TRIP-PCI Investigators |e verfasserin |4 aut | |
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