A Phase 1 Open-Label Study of the Safety of Intravenous Allogeneic Neonatal Mesenchymal Cells (nMSCs) in Young Adult (1A) and Pediatric (1B) Patients With Dilated Cardiomyopathy (DCM)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 36
- 试验地点
- 9
- 主要终点
- Proportion of participants with freedom from any Common Toxicity Criteria for Adverse Events (CTCAE) Grade 3 or greater
研究概览
简要总结
This is a Phase 1 study to determine the safety and efficacy of allogeneic neonatal mesenchymal stromal cells (nMSCs) for the treatment of Dilated Cardiomyopathy. The purpose of the study is to help doctors and scientists learn if allogeneic neonatal mesenchymal stromal cells (nMSCs) infusions are a safe and effective way to improve cardiac function and left ventricular ejection fraction.
详细描述
This study is a single site open label study with 2 phases. The 2 phases will be broken into an adult group Phase 1A with group pediatric group Phase 1B. This study will enroll patients between the ages of 4 years and 30 years old. The investigators will be looking at the safety, feasibility, and maximum tolerated dose of allogeneic neonatal mesenchymal stromal cells (nMSCs) as defined by freedom from CTCAE or Grade 3 AE that is probably or definitely related to the IP throughout the duration of the study.
A minimum of 9 and a maximum of 18 patients will be enrolled into both Phase 1A adult groups and 1B pediatric groups. Phase 1A subjects will receive study products with doses defined by the study group and Phase 1B will begin after all adult subjects have completed Phase 1A infusions, FDA and a DSMC review. Phase 1B subjects will receive study product dosed per body weight in the defined study group.
Allogeneic neonatal mesenchymal stromal cells (nMSCs) will be infused via IV every 30 days for a total of 3 infusions. There will be a baseline visit before allogeneic neonatal mesenchymal stromal cells (nMSCs) therapy is initiated, followed by a phone call 30 days after the last infusion. There will be in person visits at 3-month, 6 months, and 1 year mark. The total duration for each patient will be 14 months.
Labs will be collected at baseline, during nMSC infusions, and at in person follow up visits to assess cardiac function. Any leftover blood samples may be stored for future research by the sponsor of the study. Echocardiograms will be completed at baseline, and 3 month-, 6 month-, and 1-year visits to look at left ventricular ejection fraction and electrocardiograms will be completed to provide measures of cardiac rhythm or rhythm. Other assessments include physical exam, 6-minute walk test, Cardiac MRI, vital signs, PedsQL questionnaire for pediatrics and The Kansas City Cardiomyopathy Questionnaire for adults.
It is expected to recruit 18-36 participants through face-to-face encounters between participants and study staff during clinical encounters at Children's Healthcare of Atlanta, Emory Health care system, and Grady Health, Clinicaltrials.gov registration, and Institutional Review Board approved advertisements to surrounding hospitals with cardiac programs. Patients will also be recruited through MyChart. If identified as eligible to participate, the study team will seek approval by the subjects' primary cardiologist and consent and/or assent with the permission of the parent or legally authorized representative, will occur in person during a baseline visit.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 4 Years 至 40 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Phase 1A: Age greater than or equal to 16 years and less than 40 years (≥16 years, <40 years).
- •Phase 1B: Age greater than or equal to 4 years and less than 16 years (≥4 years, <16 years)
- •Subjects must be able to sign their own consent for Phase 1A of the study.
- •Diagnosis of dilated cardiomyopathy (DCM) defined as
- •Any Congenital Cardiac Malformation with systemic ventricular systolic dysfunction; Idiopathic Cardiomyopathy; Familial/Inherited and/or Genetic Cardiomyopathy; History of Myocarditis; Acquired (Chemotherapy, Iatrogenic, Infection, Rheumatic, Nutritional); Ischemic (e.g. Kawasaki Disease, post-operative); Left ventricular noncompaction; Coronary Artery Disease
- •Left ventricular ejection fraction less than or equal to 45% documented by two-dimensional echocardiogram or cardiac MRI within the prior six months.
- •Left ventricular dilation as defined by echocardiography left ventricular and end-diastolic dimension Z score > +2.0
- •Biventricular physiology with systemic left ventricle
- •Must receive guideline directed heart failure as defined by the American Heart Association, American College of Cardiology, and Heart Failure Society of America 118
- •Have been unresponsive or poorly responsive to at least 3 months of maximum guideline directed treatments.
排除标准
- •Listed for heart transplantation (as UNOS status 1A) or hospitalized while waiting for transplant (while on inotropes or with ventricular assist device)
- •Cardiovascular surgery of percutaneous intervention to palliate or correct congenital cardiovascular malformations within 3 months of the screening visit. Patients anticipated to undergo corrective heart surgery during the 12 months after entry into Part 1A/1B.
- •Previous heart transplant recipient
- •Unoperated primary obstructive or severe regurgitant valve (aortic, pulmonary, mitral or tricuspid) disease, or significant systemic ventricular outflow obstruction or aortic arch obstruction anticipated to require surgical or transcatheter intervention within 6 months.
- •Restrictive or hypertrophic cardiomyopathy
- •Cardiogenic shock
- •Currently on extracorporeal membrane oxygenation support
- •Ventricular assist device support
- •Lethal, uncontrollable arrhythmia defined as an arrhythmia resulting in hemodynamic instability requiring need for defibrillation, continuous intravenous anti-arrhythmic medication or mechanical circulatory support
- •Patients with persistent atrial fibrillation requiring specific pharmacotherapy
- •Amyloidosis
- •Ischemic dilated cardiomyopathy
- •Clinical history of malignant neoplasm within 5 years (with the exception of curatively treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma)
- •Serious neurologic disorder including loss of vision, stroke, or paralysis
- •High-grade pulmonary embolism requiring interventional catheter procedure or pulmonary hypertension requiring use of pulmonary vasodilators including phosphodiesterase inhibitor or nitric oxide
- •High-grade renal failure [eGFR<45] mL/min/1.73 m2 - serum potassium >5.3 mmol/L
- •Multiple organ failure
- •Non-cardiac condition that limits life span for <1 year
- •Uncontrolled diabetes (HbA1c >9%) at screening
- •Active infection (including endocarditis) requiring pharmacotherapy
- •Active hemorrhagic disease (e.g., gastrointestinal bleeding, injury)
- •History of cardiac transplantation
- •Immune system-altering medications, or immunosuppressive therapy at the time of enrolment or within the prior 12 weeks
- •Dystrophin-associated cardiomyopathy confirmed by standard cardiomyopathy panel testing
- •Confirmed myocarditis at time of screening
- •Elevated LFTs greater than 2 times upper limit of normal at time of consent
- •Elevated WBC greater than upper limit of normal as defined by local lab at time of consent
- •Presence of HLA antibodies specific for therapeutic study product
- •History of noncompliance, alcohol abuse, recreational drug use, or incarceration within the last year
- •Currently pregnant or breastfeeding
- •Unsafe/unfeasible to enroll due to PI/designee discretion
研究组 & 干预措施
Adult Cohort
Adults (≥16 years to <40 years) will be enrolled into all dose levels (as tolerated) of Phase 1A. Open label nMSCs will be administered intravenously in the following defined dose groups. The rate of infusion will be approximately 30- 60 minutes at 0, 15 and 30 days, with escalating dose levels:
- Dose level 1: 5.0x107 nMSCs at 0, 15 and 30 days
- Dose level 2: 1.0.x108 nMSCs at 0, 15 and 30 days
- Dose level 3: 2.5x108 nMSCs at 0, 15 and 30 days
Dose escalation will follow 3+3 study design parameters. The treatment between the first and second patients of each dose level will be staggered at least one month after the first patient's first infusion within each dose level. The next dosing group will be initiated at least one month after the last subject in a particular dose level has received the last dose treatment. Once MTD has been determined, 3 additional patients will be enrolled to ensure a total of 6 patients are enrolled in MTD level for confirmation.
干预措施: Allogeneic Neonatal mesenchymal stromal cells (nMSCs) (Biological)
Pediatric Cohort
Pediatric participants (4 to ≤16 years) will be enrolled as determined in Phase 1B(3+3 study design; open label). nMSCs will be administered intravenously (IV) in the following defined dose groups. The rate of infusion will be approx. 30- 60 minutes at 0, 15 and 30 days, with escalating dose levels:
- Dose Level 1: 0.7x106 nMSCs/kg
- Dose Level 2: 1.43x106 nMSCs/kg
- Dose Level 3: 2.85x106 nMSCs/kg
Dose escalation will follow 3+3 study design parameters. Treatment between 1st and 2nd patients of each dose level will be staggered at least 1 month after the 1st patient's first infusion within each dose level. The next dosing group will be initiated one month after the last subject in a particular dose level has received the last dose treatment. Once MTD has been determined, 3 additional patients will be enrolled to ensure a total of 6 patients are enrolled in MTD level for confirmation. Following IV delivery of nMSCs, patients will be followed at 3m, 6m and 1yr.
干预措施: Allogeneic Neonatal mesenchymal stromal cells (nMSCs) (Biological)
结局指标
主要结局
Proportion of participants with freedom from any Common Toxicity Criteria for Adverse Events (CTCAE) Grade 3 or greater
时间窗: End of study, around 12 months post-intervention
Proportion of participants with freedom from any Common Toxicity Criteria for Adverse Events (CTCAE) Grade 3 or greater AE that is probably or related to the IP throughout the duration of the study will be recorded. Results can vary from 0 to 100% and higher proportion correlates with better outcome. TCAE Grade 3 is defined as severe or medically significant not immediately life-threatening; hospitalization or prolongation of hospitalization. Grade 4 and 5 AEs include composite of: death, life-threatening events, initial or prolonged hospitalization, disability of permanent damage and congenital anomaly/birth defects.
Maximum tolerated dose (MTD) in patients with dilated cardiomyopathy
时间窗: End of study, around 12 months post-intervention
If two patients in a dosing group have a related SAE or Dose Limiting Toxicity (DLT), then the previous dosing group will be defined as MTD.
次要结局
- Change in quality-of-life validated survey scores in Peds Quality of Life (QOL) survey(Baseline, 3-month, 6-month and 12-month post-intervention)
- Change of left ventricular ejection fraction (LVEF) from baseline(Baseline, 3-month, 6-month, and 12-month post-intervention)
- Change in N-terminal pro b-type natriuretic peptide (NT-proBNP) levels from baseline(Baseline, 3-month, 6-month, and 12-month post-intervention)
- Change of 6-minute walk test (6MWT) results(Baseline, 3-month, 6-month, and 12-months post-intervention)
- Change in Kansas City Cardiomyopathy Questionnaire(Baseline, 3-month, 6-month and 12-month post-intervention)
研究者
William T. Mahle
Professor
Emory University