Cardiac Function Improvement and Bone Marrow Response –
Objective: The phase III clinical trial PERFECT was designed to assess clinical safety and efficacy of intramyocardial CD133+ bone marrow stem cell treatment combined with CABG for induction of cardiac repair. Design: Multicentre, double-blinded, randomised placebo controlled trial. Setting: The stu...
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Elsevier
2017-08-01
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Series: | EBioMedicine |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396417302967 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gustav Steinhoff Julia Nesteruk Markus Wolfien Günther Kundt Jochen Börgermann Robert David Jens Garbade Jana Große Axel Haverich Holger Hennig Alexander Kaminski Joachim Lotz Friedrich-Wilhelm Mohr Paula Müller Robert Oostendorp Ulrike Ruch Samir Sarikouch Anna Skorska Christof Stamm Gudrun Tiedemann Florian Mathias Wagner Olaf Wolkenhauer |
spellingShingle |
Gustav Steinhoff Julia Nesteruk Markus Wolfien Günther Kundt Jochen Börgermann Robert David Jens Garbade Jana Große Axel Haverich Holger Hennig Alexander Kaminski Joachim Lotz Friedrich-Wilhelm Mohr Paula Müller Robert Oostendorp Ulrike Ruch Samir Sarikouch Anna Skorska Christof Stamm Gudrun Tiedemann Florian Mathias Wagner Olaf Wolkenhauer Cardiac Function Improvement and Bone Marrow Response – EBioMedicine Randomised double-blinded phase III multicentre trial CD133+ CD34+ Endothelial progenitor cell (EPC) SH2B3 Lnk adaptor Cardiac repair Cardiac stem cell therapy Angiogenesis |
author_facet |
Gustav Steinhoff Julia Nesteruk Markus Wolfien Günther Kundt Jochen Börgermann Robert David Jens Garbade Jana Große Axel Haverich Holger Hennig Alexander Kaminski Joachim Lotz Friedrich-Wilhelm Mohr Paula Müller Robert Oostendorp Ulrike Ruch Samir Sarikouch Anna Skorska Christof Stamm Gudrun Tiedemann Florian Mathias Wagner Olaf Wolkenhauer |
author_sort |
Gustav Steinhoff |
title |
Cardiac Function Improvement and Bone Marrow Response – |
title_short |
Cardiac Function Improvement and Bone Marrow Response – |
title_full |
Cardiac Function Improvement and Bone Marrow Response – |
title_fullStr |
Cardiac Function Improvement and Bone Marrow Response – |
title_full_unstemmed |
Cardiac Function Improvement and Bone Marrow Response – |
title_sort |
cardiac function improvement and bone marrow response – |
publisher |
Elsevier |
series |
EBioMedicine |
issn |
2352-3964 |
publishDate |
2017-08-01 |
description |
Objective: The phase III clinical trial PERFECT was designed to assess clinical safety and efficacy of intramyocardial CD133+ bone marrow stem cell treatment combined with CABG for induction of cardiac repair.
Design: Multicentre, double-blinded, randomised placebo controlled trial.
Setting: The study was conducted across six centres in Germany October 2009 through March 2016 and stopped due slow recruitment after positive interim analysis in March 2015.
Participants: Post-infarction patients with chronic ischemia and reduced LVEF (25–50%). Interventions: Eighty-two patients were randomised to two groups receiving intramyocardial application of 5 ml placebo or a suspension of 0.5–5 × 106 CD133+.
Outcome: Primary endpoint was delta (∆) LVEF at 180 days (d) compared to baseline measured in MRI.
Findings (prespecified): Safety (n = 77): 180 d survival was 100%, MACE n = 2, SAE n = 49, without difference between placebo and CD133+. Efficacy (n = 58): The LVEF improved from baseline LVEF 33.5% by +9.6% at 180 d, p = 0.001 (n = 58). Treatment groups were not different in ∆LVEF (ANCOVA: Placebo +8.8% vs. CD133+ +10.4%, ∆CD133+vs placebo +2.6%, p = 0.4).
Findings (post hoc): Responders (R) classified by ∆LVEF ≥ 5% after 180 d were 60% of the patients (35/58) in both treatment groups. ∆LVEF in ANCOVA was +17.1% in (R) vs. non-responders (NR) (∆LVEF 0%, n = 23). NR were characterized by a preoperative response signature in peripheral blood with reduced CD133+ EPC (RvsNR: p = 0.005) and thrombocytes (p = 0.004) in contrast to increased Erythropoeitin (p = 0.02), and SH2B3 mRNA expression (p = 0.073). Actuarial computed mean survival time was 76.9 ± 3.32 months (R) vs. +72.3 ± 5.0 months (NR), HR 0.3 [Cl 0.07–1.2]; p = 0.067.Using a machine learning 20 biomarker response parameters were identified allowing preoperative discrimination with an accuracy of 80% (R) and 84% (NR) after 10-fold cross-validation.
Interpretation: The PERFECT trial analysis demonstrates that the regulation of induced cardiac repair is linked to the circulating pool of CD133+ EPC and thrombocytes, associated with SH2B3 gene expression. Based on these findings, responders to cardiac functional improvement may be identified by a peripheral blood biomarker signature.
TRIAL REGISTRATION: ClinicalTrials.gov NCT00950274. |
topic |
Randomised double-blinded phase III multicentre trial CD133+ CD34+ Endothelial progenitor cell (EPC) SH2B3 Lnk adaptor Cardiac repair Cardiac stem cell therapy Angiogenesis |
url |
http://www.sciencedirect.com/science/article/pii/S2352396417302967 |
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1725171999731351552 |
spelling |
doaj-506c8e7e8ae54a5c92e1b4df2aea82a02020-11-25T01:11:15ZengElsevierEBioMedicine2352-39642017-08-0122C20822410.1016/j.ebiom.2017.07.022Cardiac Function Improvement and Bone Marrow Response –Gustav Steinhoff0Julia Nesteruk1Markus Wolfien2Günther Kundt3Jochen Börgermann4Robert David5Jens Garbade6Jana Große7Axel Haverich8Holger Hennig9Alexander Kaminski10Joachim Lotz11Friedrich-Wilhelm Mohr12Paula Müller13Robert Oostendorp14Ulrike Ruch15Samir Sarikouch16Anna Skorska17Christof Stamm18Gudrun Tiedemann19Florian Mathias Wagner20Olaf Wolkenhauer21Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, GermanyDepartment of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, GermanyUniversity Rostock, Institute of Computer Science, Department of Systems Biology and Bioinformatics, Ulmenstraße 69, 18057 Rostock, GermanyUniversity Medicine Rostock, Department of Medical Informatics and Biostatistics, Ernst-Heydemann-Straße 8, 18055 Rostock, GermanyHeart and Diabetes Center North Rhine Westfalia, University Hospital of the Ruhr, University Bochum, Georgstraße 11, 32545 Bad Oeynhausen, GermanyDepartment of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, GermanyDepartment of Cardiac Surgery, Heart Center University Medicine Leipzig, Strümpellstraße 39, 04289 Leipzig, GermanyDepartment of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, GermanyMedical School Hannover, Department of Heart-, Thoracic-, and Vascular Surgery, Carl-Neuberg- Straße 1, 30625 Hannover, GermanyUniversity Rostock, Institute of Computer Science, Department of Systems Biology and Bioinformatics, Ulmenstraße 69, 18057 Rostock, GermanyDepartment of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, GermanyUniversity Medicine Goettingen, Department of Diagnostic Radiology, Robert-Koch-Straße 40, 37075 Göttingen, GermanyDepartment of Cardiac Surgery, Heart Center University Medicine Leipzig, Strümpellstraße 39, 04289 Leipzig, GermanyDepartment of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, GermanyDepartment of Medicine III, Technical University Munich, Klinikum rechts der Isar, Ismaninger Straße 22, 81675 München, GermanyDepartment of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, GermanyMedical School Hannover, Department of Heart-, Thoracic-, and Vascular Surgery, Carl-Neuberg- Straße 1, 30625 Hannover, GermanyDepartment of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, GermanyGerman Heart Center Berlin, Department of Heart-, Thoracic-, and Vascular Surgery, Augustenburger Platz 1, 13353 Berlin, GermanyDepartment of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, GermanyDepartment of Cardiac and Vascular Surgery, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, GermanyUniversity Rostock, Institute of Computer Science, Department of Systems Biology and Bioinformatics, Ulmenstraße 69, 18057 Rostock, GermanyObjective: The phase III clinical trial PERFECT was designed to assess clinical safety and efficacy of intramyocardial CD133+ bone marrow stem cell treatment combined with CABG for induction of cardiac repair. Design: Multicentre, double-blinded, randomised placebo controlled trial. Setting: The study was conducted across six centres in Germany October 2009 through March 2016 and stopped due slow recruitment after positive interim analysis in March 2015. Participants: Post-infarction patients with chronic ischemia and reduced LVEF (25–50%). Interventions: Eighty-two patients were randomised to two groups receiving intramyocardial application of 5 ml placebo or a suspension of 0.5–5 × 106 CD133+. Outcome: Primary endpoint was delta (∆) LVEF at 180 days (d) compared to baseline measured in MRI. Findings (prespecified): Safety (n = 77): 180 d survival was 100%, MACE n = 2, SAE n = 49, without difference between placebo and CD133+. Efficacy (n = 58): The LVEF improved from baseline LVEF 33.5% by +9.6% at 180 d, p = 0.001 (n = 58). Treatment groups were not different in ∆LVEF (ANCOVA: Placebo +8.8% vs. CD133+ +10.4%, ∆CD133+vs placebo +2.6%, p = 0.4). Findings (post hoc): Responders (R) classified by ∆LVEF ≥ 5% after 180 d were 60% of the patients (35/58) in both treatment groups. ∆LVEF in ANCOVA was +17.1% in (R) vs. non-responders (NR) (∆LVEF 0%, n = 23). NR were characterized by a preoperative response signature in peripheral blood with reduced CD133+ EPC (RvsNR: p = 0.005) and thrombocytes (p = 0.004) in contrast to increased Erythropoeitin (p = 0.02), and SH2B3 mRNA expression (p = 0.073). Actuarial computed mean survival time was 76.9 ± 3.32 months (R) vs. +72.3 ± 5.0 months (NR), HR 0.3 [Cl 0.07–1.2]; p = 0.067.Using a machine learning 20 biomarker response parameters were identified allowing preoperative discrimination with an accuracy of 80% (R) and 84% (NR) after 10-fold cross-validation. Interpretation: The PERFECT trial analysis demonstrates that the regulation of induced cardiac repair is linked to the circulating pool of CD133+ EPC and thrombocytes, associated with SH2B3 gene expression. Based on these findings, responders to cardiac functional improvement may be identified by a peripheral blood biomarker signature. TRIAL REGISTRATION: ClinicalTrials.gov NCT00950274.http://www.sciencedirect.com/science/article/pii/S2352396417302967Randomised double-blinded phase III multicentre trialCD133+CD34+Endothelial progenitor cell (EPC)SH2B3Lnk adaptorCardiac repairCardiac stem cell therapyAngiogenesis |