A Phase I/II, Randomized Pilot Study of the Comparative Safety and Efficacy of Transendocardial Injection of Autologous Mesenchymal Stem Cells Versus Allogeneic Mesenchymal Stem Cells in Patients With Non-ischemic Dilated Cardiomyopathy.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 37
- 试验地点
- 2
- 主要终点
- Incidence of Any Treatment-emergent Serious Adverse Events (TE-SAEs)
研究概览
简要总结
The technique of transplanting progenitor cells into a region of damaged myocardium, termed cellular cardiomyoplasty1, is a potentially new therapeutic modality designed to replace or repair necrotic, scarred, or dysfunctional myocardium2-4. Ideally, graft cells should be readily available, easy to culture to ensure adequate quantities for transplantation, and able to survive in host myocardium; often a hostile environment of limited blood supply and immunorejection. Whether effective cellular regenerative strategies require that administered cells differentiate into adult cardiomyocytes and couple electromechanically with the surrounding myocardium is increasingly controversial and recent evidence suggests that this may not be required for effective cardiac repair. Most importantly, transplantation of graft cells should improve cardiac function and prevent adverse ventricular remodeling. To date, a number of candidate cells have been transplanted in experimental models, including fetal and neonatal cardiomyocytes5, embryonic stem cell-derived myocytes6, 7, tissue engineered contractile grafts8, skeletal myoblasts9, several cell types derived from adult bone marrow10-15, and cardiac precursors residing within the heart itself16. There has been substantial clinical development in the use of whole bone marrow and skeletal myoblast preparations in studies enrolling both post-infarction patients, and patients with chronic ischemic left ventricular dysfunction and heart failure. The effects of bone-marrow derived mesenchymal stem cells (MSCs) have also been studied clinically.
Currently, bone marrow or bone marrow-derived cells represent highly promising modality for cardiac repair. The totality of evidence from trials investigating autologous whole bone marrow infusions into patients following myocardial infarction supports the safety of this approach. In terms of efficacy, increases in ejection fraction are reported in the majority of the trials.
Non-ischemic dilated cardiomyopathy is a common and problematic condition; definitive therapy in the form of heart transplantation is available to only a tiny minority of eligible patients. Cellular cardiomyoplasty for chronic heart failure has been studied less than for acute MI, but represents a potentially important alternative for this disease.
详细描述
This is a Pilot Study, intended as a safety assessment prior to a full comparator study. In this Pilot Study, cells administered via the Biosense Webster MyoStar NOGA injection catheter system will be tested in 36 patients in two groups:
Group 1 (18 patients) Eighteen (18) patients will be treated with Auto-hMSCs: 20 million cells/ml delivered in a dose of 0.5 ml per injection x 10 injections for a total of 1 X 108 (100 million) Auto-hMSCs.
Group 2 (18 patients) Eighteen (18) patients will be treated with Allo-hMSCs: 20 million cells/ml delivered in a dose of 0.5 ml per injection x 10 injections for a total of 1 X 108 (100 million) Auto-hMSCs.
The first three (3) patients in each group (Group 1 and Group 2) will not be treated less than 5 days apart and will each undergo full evaluation for 5 days to demonstrate there is no evidence of a procedure induced myocardial infarction or myocardial perforation prior to proceeding with the treatment of further patients.
Patients will be randomized in a 1:1 ratio to one of the two groups.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 95 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Be ≥ 18 and < 95 years of age.
- •Provide written informed consent.
- •Diagnosis of nonischemic dilated cardiomyopathy.
- •Be a candidate for cardiac catheterization within 5 to 10 weeks of screening.
- •Been treated with appropriate maximal medical therapy for heart failure.
- •Ejection fraction below 40% and either a left ventricular end diastolic diameter (LVEDD) > 5.9cm in male subjects, an LVEDD of > 5.6cm in female subjects or left ventricular end diastolic volume index > 125 mL/m2
- •Be able to undergo an MRI or CT.
排除标准
- •Baseline glomerular filtration rate equal or < 45 ml/min/1.73m
- •Be eligible for or require standard-of-care surgical or percutaneous intervention for the treatment of nonischemic dilated cardiomyopathy.
- •Presence of a prosthetic aortic valve or heart constrictive device.
- •Presence of a prosthetic mitral valve.
- •Previous myocardial infarction (MI) as documented by a clinical history that will include an elevation of cardiac enzymes and/or ECG changes consistent with MI.
- •Diagnosis of nonischemic dilated cardiomyopathy due to valvular dysfunction, mitral regurgitation, tachycardia, or myocarditis.
- •Previous treatment for post-infarction left ventricular dysfunction including PCI and thrombolytic therapy.
- •Documented presence of a known LV thrombus, aortic dissection, or aortic aneurysm.
- •Documented presence of epicardial stenosis of 70% or greater in one or more major epicardial coronary arteries.
- •Documented presence of aortic stenosis (aortic stenosis graded as 1.5cm2 or less).
- •Documented presence of moderate to severe aortic insufficiency (echocardiographic assessment of aortic insufficiency graded as ≥+2).
- •Evidence of a life-threatening arrhythmia in the absence of a defibrillator (nonsustained ventricular tachycardia ≥ 20 consecutive beats or complete second or third degree heart block in the absence of a functioning pacemaker) or QTc interval > 550 ms on screening ECG.
- •AICD firing in the past 30 days prior to the procedure
- •Be eligible for or require coronary artery revascularization.
- •Diabetic with poorly controlled blood glucose levels and/or evidence of proliferative retinopathy.
- •Have a hematologic abnormality as evidenced by hematocrit < 25%, white blood cell < 2,500/ul or platelet values < 100,000/ul without another explanation.
- •Have liver dysfunction, as evidenced by enzymes (ALT and AST) greater than three times the ULN.
- •Have a coagulopathy condition = (INR > 1.3) not due to a reversible cause.
- •Known, serious radiographic contrast allergy.
- •Known allergies to penicillin or streptomycin.
- •Organ transplant recipient.
- •Have a history of organ or cell transplant rejection
- •Clinical history of malignancy within 5 years (i.e., patients with prior malignancy must be disease free for 5 years), except curatively-treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma.
- •Non-cardiac condition that limits lifespan to < 1 year.
- •On chronic therapy with immunosuppressant medication.
- •Serum positive for HIV, hepatitis BsAg, or viremic hepatitis C.
- •Female patient who is pregnant, nursing, or of child-bearing potential and not using effective birth control.
- •Have a history of drug or alcohol abuse within the past 24 months.
- •Be currently participating (or participated within the previous 30 days) in an investigational therapeutic or device trial.
研究组 & 干预措施
Autologous hMSCs
Group 1 (18 patients) Eighteen (18) patients will be treated with Auto-hMSCs: 20 million cells/ml delivered in a dose of 0.5 ml per injection x 10 injections for a total of 1 x 108 (100 million) Auto-hMSCs.
干预措施: Autologous hMSCs (Biological)
Allogeneic hMSCs
Group 2 (18 patients) Eighteen (18) patients will be treated with allogeneic hMSCs (Allo-hMSCs): 20 million cells/ml delivered in a dose of 0.5 ml per injection x 10 injections for a total of 1 x 108 (100 million) Auto-hMSCs.
干预措施: Allogeneic hMSCs (Biological)
结局指标
主要结局
Incidence of Any Treatment-emergent Serious Adverse Events (TE-SAEs)
时间窗: One month post-catheterization
Incidence of TE-SAEs is defined as the composite of: death, non-fatal MI, stroke, hospitalization for worsening heart failure, cardiac perforation, pericardial tamponade, sustained ventricular arrhythmias (characterized by ventricular arrhythmias lasting longer than 15 seconds or with hemodynamic compromise), or any other potential late effects detected and corroborated by clinical presentation, laboratory investigations, image analysis and when necessary with biopsy from suspected target sites in the body.
次要结局
- Measurement of Changes in Peak VO2(Baseline, 6 month and 12 month)
- Measurement of Changes in 6 Minute Walk(Baseline, 6 month and 12 month)
- Measurement of Changes in Global Ejection Fraction(Baseline, 6 month and 12 month)
- Measurement of Changes in New York Heart Association (NYHA)(Baseline, 6 month and 12 month)
- Measurement of Changes in Minnesota Living With Heart Failure (MLHF) Questionnaire(Baseline, 6 month and 12 month)
研究者
Joshua M Hare
Sponsor- Investigator; Director of ISCI, Chief Science Officer
University of Miami