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EBioMedicine. 2017 Aug;22:208-224. doi: 10.1016/j.ebiom.2017.07.022. Epub 2017 Jul 29.

Cardiac Function Improvement and Bone Marrow Response -: Outcome Analysis of the Randomized PERFECT Phase III Clinical Trial of Intramyocardial CD133+ Application After Myocardial Infarction.

Author information

1
Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany. Electronic address: gustav.steinhoff@med.uni-rostock.de.
2
Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany. Electronic address: iuliia.nesteruk@med.uni-rostock.de.
3
University Rostock, Institute of Computer Science, Department of Systems Biology and Bioinformatics, Ulmenstraße 69, 18057 Rostock, Germany. Electronic address: markus.wolfien@uni-rostock.de.
4
University Medicine Rostock, Department of Medical Informatics and Biostatistics, Ernst-Heydemann-Straße 8, 18055 Rostock, Germany. Electronic address: guenther.kundt@med.uni-rostock.de.
5
Heart and Diabetes Center North Rhine Westfalia, University Hospital of the Ruhr, University Bochum, Georgstraße 11, 32545 Bad Oeynhausen, Germany. Electronic address: jboergermann@hdz-nrw.de.
6
Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany. Electronic address: robert.david@med.uni-rostock.de.
7
Department of Cardiac Surgery, Heart Center University Medicine Leipzig, Strümpellstraße 39, 04289 Leipzig, Germany. Electronic address: jens.garbade@helios-kliniken.de.
8
Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany. Electronic address: jana.grosse@med.uni-rostock.de.
9
Medical School Hannover, Department of Heart-, Thoracic-, and Vascular Surgery, Carl-Neuberg- Straße 1, 30625 Hannover, Germany. Electronic address: haverich.axel@mh-hannover.de.
10
University Rostock, Institute of Computer Science, Department of Systems Biology and Bioinformatics, Ulmenstraße 69, 18057 Rostock, Germany; Broad Institute of Harvard and MIT, Imaging Platform, 415 Main St, Cambridge, MA 02142, USA. Electronic address: holger.hennig@uni-rostock.de.
11
Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany. Electronic address: alexander.kaminski@med.uni-rostock.de.
12
University Medicine Goettingen, Department of Diagnostic Radiology, Robert-Koch-Straße 40, 37075 Göttingen, Germany. Electronic address: joachim.lotz@med.uni-goettingen.de.
13
Department of Cardiac Surgery, Heart Center University Medicine Leipzig, Strümpellstraße 39, 04289 Leipzig, Germany. Electronic address: chir@herzzentrum-leipzig.de.
14
Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany. Electronic address: paula.mueller@med.uni-rostock.de.
15
Department of Medicine III, Technical University Munich, Klinikum rechts der Isar, Ismaninger Straße 22, 81675 München, Germany. Electronic address: robert.oostendorp@tum.de.
16
Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany. Electronic address: ulrike.ruch@med.uni-rostock.de.
17
Medical School Hannover, Department of Heart-, Thoracic-, and Vascular Surgery, Carl-Neuberg- Straße 1, 30625 Hannover, Germany.
18
Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany. Electronic address: anna.skorska@med.uni-rostock.de.
19
German Heart Center Berlin, Department of Heart-, Thoracic-, and Vascular Surgery, Augustenburger Platz 1, 13353 Berlin, Germany. Electronic address: stamm@DHZB.de.
20
Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany. Electronic address: gudrun.tiedemann@web.de.
21
Department of Cardiac and Vascular Surgery, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany. Electronic address: fl.wagner@uke.de.
22
University Rostock, Institute of Computer Science, Department of Systems Biology and Bioinformatics, Ulmenstraße 69, 18057 Rostock, Germany. Electronic address: olaf.wolkenhauer@uni-rostock.de.

Abstract

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 5ml placebo or a suspension of 0.5-5×106 CD133+.

OUTCOME:

Primary endpoint was delta (∆) LVEF at 180days (d) compared to baseline measured in MRI.

FINDINGS (PRESPECIFIED):

Safety (n=77): 180d 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 180d, 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 180d 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±3.32months (R) vs. +72.3±5.0months (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.govNCT00950274.

KEYWORDS:

Angiogenesis; CD133(+); CD34(+); Cardiac repair; Cardiac stem cell therapy; Endothelial progenitor cell (EPC); Lnk adaptor; Randomised double-blinded phase III multicentre trial; SH2B3

PMID:
28781130
PMCID:
PMC5552265
DOI:
10.1016/j.ebiom.2017.07.022
[Indexed for MEDLINE]
Free PMC Article

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