Randomised, double-blind, placebo-controlled clinical trial for evaluating the efficacy of intracoronary injection of autologous bone marrow mononuclear cells in the improvement of the ventricular function in patients with idiopathic dilated myocardiopathy: a study protocol

Abstract

Background: Cellular therapies have been increasingly applied to diverse human diseases. Intracoronary infusion of bone marrow-derived mononuclear cells (BMMNC) has demonstrated to improve ventricular function after acute myocardial infarction. However, less information is available about the role of BMMNC therapy for the treatment of dilated myocardiopathies (DCs) of non-ischemic origin. This article presents the methodological description of a study aimed at investigating the efficacy of intracoronary injection of autologous BMMNCs in the improvement of the ventricular function of patients with DC.

Methods: This randomised, placebo-controlled, double-blinded phase IIb clinical trial compares the improvement on ventricular function (measured by the changes on the ejection fraction) of patients receiving the conventional treatment for DC in combination with a single dose of an intracoronary infusion of BMMNCs, with the functional recovery of patients receiving placebo plus conventional treatment. Patients assigned to both treatment groups are monitored for 24 months. This clinical trial is powered enough to detect a change in Left Ventricular Ejection Fraction (LVEF) equal to or greater than 9%, although an interim analysis is planned to re-calculate sample size.

Discussion: The study protocol was approved by the Andalusian Coordinating Ethics Committee for Biomedical Research (Comité Coordinador de Ética en Investigación Biomédica de Andalucia), the Spanish Medicines and Medical Devices Agency (Agencia Española de Medicamentos y Productos Sanitarios), and is registered at the EU Clinical Trials Register (EudraCT: 2013-002015-98). The publication of the trial results in scientific journals will be performed in accordance with the applicable regulations and guidelines to clinical trials.

Trial registration: ClinicalTrials.gov Identifier NCT02033278 (First Posted January 10, 2014): https://ichgcp.net/clinical-trials-registry/NCT02033278 ; EudraCT number: 2013-002015-98, EU CT Register: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-002015-98 . Trial results will also be published according to the CONSORT statement at conferences and reported peer-reviewed journals.

Keywords: Bone marrow mononuclear cells; Cell therapy; Dilated myocardiopathy; Randomized controlled trial.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1

Study design and assessment timeline. Clinical trial visits are structured in 9 time-points, that include two pre-infusion visits (screening and randomization), BMMNC/placebo infusion day, and 6 post-infusion follow-up evaluation time-points according to a decreasing frequency: 24 h, 3 months, 6 months, 12 months, 18 months and 24 months. The procedures and evaluations performed are detailed for each visit. Biochemical determinations: glucose, urea, creatinine, sodium, potassium, C reactive protein (CRP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), bilirubin, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, lactate dehydrogenase (LDH). Cardiac enzymes: Creatine kinase (CK), Troponin I or US and brain natriuretic peptide (BNP) or N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP). Demographic data: date of born, sex. Echocardiogram (Echo): Left ventricular (LV) ejection fraction (LVEF, %), LV end-diastolic volume (LVEDV, ml), LV end-systolic volume (LVESV, ml), LV end-diastolic diameter (LVED, mm), LV end-systolic diameter (LVSD, mm), left atrial (LA) area (cm2), right ventricular (RV) end-diastolic volume (RVEDV, ml), Tricuspid annular plane systolic excursion (TAPSE, mm). Electrocardiogram (ECG): synusal rhythm, conduction disturbances, atrial fibrillation (AF), right bundle branch block (RBBB), left bundle branch block (LBBB), left anterior hemiblock (LAHB), QRS duration (sec), PR duration (sec), heart rate (bpm). Exercise testing (ExTest) (according to Naughton protocol): Metabolic equivalents (METS), exercise time (min). Hemogram: red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell (WBC) count (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), erythrocyte sedimentation rate (ESR), platelets. Medical history: personal antecedents, cardiovascular risk factors (hypertension, dyslipidemia, tobacco and alcohol consumption, history of ischemic cardiomyopathy). Clinical evaluation: adverse events (AEs), concomitant drugs and procedures evaluation. Serology: human immunodeficiency virus (HIV), Hepatitis B virus (HBV), Hepatitis C virus (HCV). Tumoral markers: CA125, CA19.9, carcinoembryonic antigen (CEA), and alpha-fetoprotein (AFP), Beta-hCG (BHCG), prostate-specific antigen (PSA). Ventriculography: LVEF in sinus rhythm (%), LVEF in sinus rhythm post-PVC (premature ventricular contraction) (%), Sinus end-diastolic volume (mL/m2), Sinus end-systolic volume (mL/m2), Post-PVC end-diastolic volume (mL/m2), Post-PVC end-systolic volume (mL/m2), hypokinesia in sinus rhythm, hypokinesia post-PVC, acute coronary syndrome (ACS) in sinus rhythm, ACS post-PVC, left ventricular end-diastolic pressure and heart rate (bpm). Vital signs: blood pressure (mmHg), heart rate (bpm)