Randomized trial of combination cytokine and adult autologous bone marrow progenitor cell administration in patients with non-ischaemic dilated cardiomyopathy: the REGENERATE-DCM clinical trial

Abstract

AimsThe REGENERATE-DCM trial is the first phase II randomized, placebo-controlled trial aiming to assess if granulocyte colony-stimulating factor (G-CSF) administration with or without adjunctive intracoronary (IC) delivery of autologous bone marrow-derived cells (BMCs) improves global left ventricular (LV) function in patients with dilated cardiomyopathy (DCM) and significant cardiac dysfunction.Methods and resultsSixty patients with DCM and left ventricular ejection fraction (LVEF) at referral of ≤45%, New York Heart Association (NYHA) classification ≥2 and no secondary cause for the cardiomyopathy were randomized equally into four groups: peripheral placebo (saline), peripheral G-CSF, peripheral G-CSF and IC serum, and peripheral G-CSF and IC BMC. All patients, except the peripheral placebo group, received 5 days of G-CSF. In the IC groups, this was followed by bone marrow harvest and IC infusion of cells or serum on Day 6. The primary endpoint was LVEF change from baseline to 3 months, determined by advanced cardiac imaging. At 3 months, peripheral G-CSF combined with IC BMC therapy was associated with a 5.37% point increase in LVEF (38.30% ± 12.97 from 32.93% ± 16.46 P = 0.0138), which was maintained to 1 year. This was associated with a decrease in NYHA classification, reduced NT-pro BNP, and improved exercise capacity and quality of life. No significant change in LVEF was seen in the remaining treatment groups.ConclusionThis is the first randomized, placebo-controlled trial with a novel combination of G-CSF and IC cell therapy that demonstrates an improvement in cardiac function, symptoms, and biochemical parameters in patients with DCM.

Bone marrow‐derived mononuclear cell therapy for nonischaemic dilated cardiomyopathy—A meta‐analysis

“…The designs and the basal characteristics of selected trials are summarized in Table . Two trials are 4‐arm comparison. The REGENERATE‐DCM trial had 4 groups included as follows: (i) a group received peripheral subcutaneous injected saline; (ii) a group received subcutaneous G‐CSF; (iii) a group who underwent bone marrow harvest using G‐CSF and received IC infusion of autologous BMMCs and (iv) a group who underwent bone marrow harvest using G‐CSF but received IC infusion of serum only.…”

Towards the standardization of stem cell therapy studies for ischemic heart diseases: Bridging the gap between animal models and the clinical setting

“…Even in clinical trials, structural and functional parameters, carried out by several imaging techniques, remain as conventional endpoints. A significant part of the clinical trials do not resort to any kind of molecular monitoring [81][82][83][84]88,89,92,94] and when they do, they are limited to some conventional cardiac markers (Table 1), mainly BNP [90,96], NT-proBNP [77][78][79][80]86,87,91,93], in addition to creatine kinase [77,86,87,90,[95][96][97], troponins I [90,96,97] and T [77,80,86,87] and some inflammation markers, such as TNF-α, IL-6 [79] and C-reactive protein [77,86]. Therefore, we suggest to screen biofluids (Box 5, Fig.…”

Challenges to success in heart failure: Cardiac cell therapies in patients with heart diseases

“…Although 4 patients died during a 6-month follow-up period, a small but significant increase in ejection fraction and cardiac volume, as well as clinical symptom improvements, were found in surviving patients, compared with controls, of whom 2 patients died during the observation period. The REGENERATE-DCM (bone marrow derived adult stem cells for dilated cardiomyopathy) trial is another randomized study with encouraging results, but was not included in the meta-analysis results described above due to the study design using a combination use of bone marrow stem cells and granulocyte colony stimulating factor (GCSF) [58]. Clinical trials involving DCM patients are currently in progress, including a phase I/II trial of autologous mesenchymal stem cells, the POSEIDON-DCM study (percutaneous stem cell injection delivery effects on neomyogenesis in dilated cardiomyopathy: NCT01392625), and a phase I trial of allogeneic CDCs, the DYNAMIC study (dilated cardiomyopathy intervention with allogeneic myocardially regenerative cells) that employs a less invasive approach using a non-occlusive intracoronary infusion technique [59] (Table 2).…”