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

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 × 10(6) 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.govNCT00950274.