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

EBioMedicine
Authors
Keywords
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 0.5-5×10 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%, ∆CD133vs 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.

Year of Publication
2017
Journal
EBioMedicine
Volume
22
Pages
208-224
Date Published
2017 Aug
ISSN
2352-3964
DOI
10.1016/j.ebiom.2017.07.022
PubMed ID
28781130
PubMed Central ID
PMC5552265
Links