Abstract
BackgroundRegenerative therapies offer new approaches to improve cardiac function after acute ST-elevation myocardial infarction (STEMI). Previous trials using bone marrow cells, selected stem cell populations, or cardiac stem cell progenitors require invasive procedures and had so far inconclusive results. A less invasive approach utilizes granulocyte-colony stimulating factor (G-CSF) to mobilize stem cells to circulating blood and induce neovascularization and differentiation into endothelial cells and cardiomyocytes. Stromal cell-derived factor 1 alpha (SDF-1α) is an important chemokine for initiating stem cell migration and homing to ischemic myocardium. SDF-1α concentrations can be increased by inhibition of CD26/DPP4. Dutogliptin, a novel DPP4 inhibitor, combined with stem cell mobilization using G-CSF significantly improved survival and reduced infarct size in a murine model.MethodsWe test the safety and tolerability and efficacy of dutogliptin in combination with filgrastim (G-CSF) in patients with STEMI (EF < 45%) following percutaneous coronary intervention (PCI). Preliminary efficacy will be analyzed using cardiac magnetic resonance imaging (cMRI) to detect > 3.8% improvement in left ventricular ejection fraction (LV-EF) compared to placebo. One hundred forty subjects will be randomized to filgrastim plus dutogliptin or matching placebos.DiscussionThe REC-DUT-002 trial is the first to evaluate dutogliptin in combination with G-CSF in patients with STEMI. Results will lay the foundation for an appropriately powered cardiovascular outcome trial to test the efficacy of this combined pharmacological strategy.Trial registrationEudraCT no.: 2018-000916-75. Registered on 7 June 2018. IND number: 123717
Highlights
Background and rationale {6a} Regenerative therapies for the treatment of patients with cardiovascular diseases have the potential to improve cardiac function, quality of life, and survival, and offer a new approach to mitigating myocardial injury after acute ST-elevation myocardial infarction (STEMI) [1]
Objectives {7} The primary objective of the study is to evaluate the efficacy of dutogliptin in combination with filgrastim in patients with STEMI compared to placebo
Outcomes {12} The primary objective of the study is to evaluate the efficacy of dutogliptin in combination with filgrastim in patients with STEMI compared to placebo
Summary
Background and rationale {6a} Regenerative therapies for the treatment of patients with cardiovascular diseases have the potential to improve cardiac function, quality of life, and survival, and offer a new approach to mitigating myocardial injury after acute ST-elevation myocardial infarction (STEMI) [1]. The use of 2nd generation stem cells, such as selected stem cell populations [6] or cardiac stem cell progenitors [7], reported promising results but has not undergone rigorous testing All these approaches require invasive stem cell harvest via bone marrow biopsy or apheresis and invasive intracoronary or myocardial administration. A less invasive approach is to utilize granulocyte-colony stimulating factor (G-CSF) after STEMI to increase the release of bone marrow stem cells into the circulation. Previous trials using bone marrow cells, selected stem cell populations, or cardiac stem cell progenitors require invasive procedures and had so far inconclusive results. A less invasive approach utilizes granulocyte-colony stimulating factor (G-CSF) to mobilize stem cells to circulating blood and induce neovascularization and differentiation into endothelial cells and cardiomyocytes. Dutogliptin, a novel DPP4 inhibitor, combined with stem cell mobilization using G-CSF significantly improved survival and reduced infarct size in a murine model
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