Phase IIb Multicenter Double-Blind Randomized Placebo-Controlled Trial of Intracoronary Autologous Bone Marrow-Derived Mononuclear Cells in Idiopathic Dilated Cardiomyopathy

The primary objective of this clinical trial is to evaluate the **efficacy** of intracoronary injection of autologous bone marrow mononucleated cells (BMMNCs) in improving ventricular function among patients with idiopathic dilated cardiomyopathy, a condition for which there is currently no effective therapeutic alternative. This objective is clinically relevant as it addresses the need for novel treatment strategies in managing heart failure associated with idiopathic dilated cardiomyopathy, potentially offering a new therapeutic avenue for patients who lack effective options.

Secondary objectives include: - Analyzing the predictors of good clinical response, functional and biological treatment with adult stem cells autologous mononuclear bone marrow not expanded in terms of functional recovery. - Determining the application protocol suitable for cell therapy in the treatment of idiopathic dilated cardiomyopathy, focusing on the ideal characteristics of the bone marrow graft and identifying patients most likely to benefit, with the aim of establishing a definitive strategy for including cell therapy in standard treatment if results are favorable. - Confirming product safety and the route of administration, as demonstrated in previous studies.

The clinical trial focuses on patients diagnosed with **idiopathic dilated cardiomyopathy**, a condition characterized by the enlargement and weakening of the heart's ventricles. The study population includes both male and female participants aged between 18 and 70 years. Participants are required to have a stable medical therapy for at least six months prior to enrollment, and they must exhibit a left ventricular ejection fraction (LVEF) of less than 40%, or between 40% and 50% if the left ventricular end-diastolic volume (LVEDV) exceeds 110 ml/m², as measured by echocardiogram. The trial excludes individuals with coronary lesions, as confirmed by multislice CT or hemodynamic study, unless they have a clinical profile with a very low risk of such lesions. Participants must maintain sinus rhythm and have normal laboratory parameters, including specific thresholds for white blood cells, neutrophils, platelets, AST/ALT, creatinine, and hemoglobin. Women of childbearing age are required to have a negative pregnancy test and agree to use a medically approved method of contraception during the study. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy of intracoronary infusion of **autologous bone marrow-derived adult mononuclear cells** in patients with **idiopathic dilated cardiomyopathy**. The trial aims to assess improvements in ventricular function, with the primary endpoint being changes determined angiographically. Secondary endpoints include clinical evaluations, echocardiographic assessments, and the absence of major cardiac events. The trial is expected to conclude by September 2025, with recruitment having commenced in February 2014.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, sex, and medical history. Key inclusion criteria include patients aged 18 to 70 years, a diagnosis of idiopathic dilated cardiomyopathy established by echocardiography, and stable medical therapy for at least six months. Women of childbearing potential must have a negative pregnancy test and agree to use effective contraception. Exclusion criteria are not specified in the provided data.

Following the screening visit, participants will be randomized to receive either the investigational product or placebo. The investigational product is administered as a **suspension for injection** via intracoronary use. The trial involves multiple follow-up visits to monitor safety and efficacy, including clinical evaluations, laboratory tests, and imaging studies. The end-of-study visit will assess the overall outcomes and any adverse events experienced during the trial.

Participant involvement is expected to last until the end of the study in 2025, unless early termination is warranted. Conditions for early termination may include the occurrence of significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial is conducted under strict ethical guidelines, ensuring informed consent and adherence to regulatory standards.

The clinical trial involves the administration of **autologous bone marrow-derived adult mononuclear cells, not expanded**. This experimental medication is provided in the form of a **suspension for injection**. The route of administration is **intracoronary use**, which involves delivering the cells directly into the coronary arteries. The maximum daily and total dose is set at 1,000,000,000 cells, administered over a treatment period of one day. The cells are derived from the patient's own bone marrow, ensuring they are autologous and not expanded prior to administration. This advanced therapy medicinal product is developed by the RED ANDALUZA DE DISEÑO Y TRASLACIÓN DE TERAPIAS AVANZADAS - FUNDACIÓN PROGRESO Y SALUD.

The trial also includes a **placebo** group to serve as a comparator. The placebo is designed to mimic the experimental treatment in appearance and administration route, ensuring the study remains double-blind. The placebo does not contain any active substances and is used to assess the efficacy of the experimental treatment by providing a baseline for comparison. The pharmaceutical form and specific characteristics of the placebo are not detailed, but it is administered in a manner consistent with the experimental treatment to maintain the integrity of the study design.

The efficacy of the clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint focuses on changes in ventricular function, which will be determined angiographically. This method provides a direct assessment of the heart's pumping ability and structural changes over the course of the trial.

Secondary endpoints encompass a range of clinical and laboratory evaluations. These include changes in clinical evaluation and determination of the New York Heart Association (NYHA) functional class, levels of **B-type Natriuretic Peptide (BNP)** or its NT-proBNP fragment, and results from a full echocardiogram. Additionally, the assessment of functional capacity will be conducted through an exercise test without measuring oxygen consumption, and cardiac catheterization will be performed. The trial will also monitor the evolution time from the diagnosis of idiopathic dilated cardiomyopathy to the inclusion of the patient in the clinical trial.

Further secondary endpoints involve evaluating the degree of clinical improvement based on the absence of major cardiac events (MACE) during follow-up, such as severe arrhythmias, all-cause death, cardiac death, cardiac hospitalization, and inclusion in the heart transplantation waiting list. The presence or absence of symptoms or arrhythmias and the clinical functional degree will be closely monitored through frequent telephone calls and periodic hospital check-ups on an outpatient basis.

Laboratory assessments related to the cellular therapy medicinal product will include automatic cell counting to determine the total cellularity infused, analysis of the cellular composition in terms of progenitor content, expression of adhesion molecules, contamination of red blood cells, and expression of various membrane markers. Functional analysis of the chemotactic capacity of the infused cells will also be conducted. These comprehensive assessments will provide a robust evaluation of the efficacy of the intracoronary infusion of autologous bone marrow-derived adult mononuclear cells in patients with idiopathic dilated cardiomyopathy and heart failure.