A Randomized, Double-blind, Placebo-controlled, Phase I Study of the Safety of Multi-vessel Intra-coronary Delivery of Allogeneic Human Cardiosphere-Derived Stem Cells in Patients With Dilated Cardiomyopathy (DCM)
试验速览
- 阶段
- 1 期
- 入组人数
- 42
- 试验地点
- 1
- 主要终点
- Proportion of subjects that experience new TIMI flow 0-2 or TIMI myocardial perfusion grade (TMPG) 0-2.
研究概览
简要总结
To determine the safety profile of CAP-1002 administered by multi-vessel intracoronary infusion in subjects with DCM. The study will further explore safety and exploratory efficacy endpoints of CAP-1002.
详细描述
Eligible subjects will undergo sequential intracoronary infusion of CAP-1002 or placebo in up to three coronary arteries supplying three major cardiac territories to the heart (anterior, lateral, inferior/posterior). After completion of the screening procedures, Phase Ia subjects will receive CAP-1002 administered via intracoronary infusion in a dose escalation, stepwise manner. Phase Ia subjects will be followed at Week 2 and at Months 1, 2, 3, 6 and 12 after CAP-1002 infusion. The first fourteen (14) subjects will receive intracoronary infusion of CAP-1002 in an open-label fashion (Phase Ia). Once all 14 subjects in the Phase Ia have reached the primary safety endpoint (1 month visit), the DSMB will conduct a review of the Phase Ia data and recommend whether to proceed with enrollment of the next 28 subjects in the Phase Ib.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Major Inclusion Criteria:
- •DCM with left ventricular ejection fraction (LVEF) ≤ 35% as determined by a historical TTE within the previous 6 months
- •New York Heart Association (NYHA) Class III or ambulatory Class IV heart failure
- •Use of evidence based medical-therapy (beta-blockers, ACE-inhibitors/angiotensin receptor blockers, aldosterone antagonist) and with or without device-therapy (Implantable cardioverter-defibrillator or cardiac resynchronizing therapy), in accordance with the ACC/AHA guidelines for the management of heart failure, for at least three months prior to enrollment or documented contraindication or intolerance or patient preference
- •Coronary anatomy suitable for Investigational Product (IP) infusion, as determined by the Eligibility Committee (a team of cardiology experts)
- •Ability to provide informed consent and follow-up with protocol procedures
- •Screening cardiac CT left ventriculogram ejection fraction <40% with left ventricular dilatation
- •Age ≥ 18 years
排除标准
- •Diagnosis of active myocarditis
- •Immunologic incompatibility with all available Master Cell Banks (MCBs) by single-antigen bead (SAB) serum antibody profiling
- •Left Ventricular Assist Devices (LVAD) or those actively in the process of acquiring one
- •Recent placement of a cardiac pacemaker and/or resynchronization pacing therapy within the past three months or those actively in the process of acquiring one
- •History of sustained ventricular tachycardia (VT) requiring cardiopulmonary resuscitation (with the exception of subjects who subsequently received an ICD)
- •Non-cardiovascular disease with life expectancy of < 3 years
- •Known hypersensitivity to contrast agents
- •Estimated glomerular filtration rate (GFR) < 50 mL/min
- •Active infection not responsive to treatment
- •Active allergic reactions, connective tissue disease or autoimmune disorders
- •History of cardiac tumor, or cardiac tumor demonstrated on screening
- •History of previous stem cell therapy
- •History of treatment with immunosuppressive agents, including chronic systemic corticosteroids, biologic agents targeting the immune system, anti-tumor and anti-neoplastic drugs or anti-vascular endothelial growth factor (VEGF) within 6 months prior to enrollment (not including drug eluting coronary stents)
- •History of receipt of chemotherapeutic agents known to be implicated in cardiac dysfunction [Adriamycin, trastuzumab (Herceptin)]
- •Known moderate-severe aortic stenosis/insufficiency or severe mitral stenosis/regurgitation
- •Participation in an on-going protocol studying an experimental drug or device
- •Current active alcohol or drug abuse or inability to comply with protocol-related procedures
- •Pregnant/nursing women and women of child-bearing potential without use of active and highly reliable contraception
- •Known history of Human Immunodeficiency Virus (HIV) infection
- •Known history of chronic viral hepatitis
- •Abnormal liver function (serum glutamic pyruvic transaminase (SGPT) > 10 times the upper reference range) and/or abnormal hematology (hematocrit < 25%, white blood cells (WBC) < 3000 µl, platelets < 100,000 µl) studies without a reversible, identifiable cause
- •Evidence of tumor on screening of chest/abdominal/pelvic (body) CT scan
- •Any prior organ transplant
- •Being actively listed for, or under active consideration (i.e., work-up) for, a solid organ transplant of any kind
- •Known hypersensitivity to bovine products
- •Known hypersensitivity to dimethyl sulfoxide (DMSO)
- •Any malignancy within past 2 years (except for in-situ non-melanoma skin cancer and in-situ cervical cancer)
- •Any prior radiation therapy/treatment to the chest
- •Uncontrolled diabetes (HbA1 >9.0)
- •Any condition or other reason that, in the opinion of the Investigator or Medical Monitor, would render the subject unsuitable for the study
研究组 & 干预措施
Allogeneic Cardiosphere-Derived Cells
The Phase I study consists of a Phase Ia portion and a Phase Ib portion. The Phase Ia portion (N=14 subjects) consists of an open-label, single-arm, study design. The potentially conducted Phase Ib portion of the study (N=28 subjects) consists of a double-blind, randomized, placebo-controlled study design.
The Phase Ia portion is an open-label, dose escalation of Allogeneic Cardiosphere-Derived Cells (CDCs).
干预措施: Allogeneic Cardiosphere-Derived Cells (CDCs) (Biological)
Placebo
The placebo study arm only applies to the Phase Ib portion of the study design. The Phase Ia portion (N=14 subjects) consists of an open-label, single-arm, study design. The potentially conducted Phase Ib portion of the study (N=28 subjects) consists of a double-blind, randomized, placebo-controlled study design.
干预措施: Allogeneic Cardiosphere-Derived Cells (CDCs) (Biological)
结局指标
主要结局
Proportion of subjects that experience new TIMI flow 0-2 or TIMI myocardial perfusion grade (TMPG) 0-2.
时间窗: Intraprocedural
Proportion of subjects that experience acute myocarditis, possibly attributable to CAP-1002. In order to be considered related to CAP-1002, humoral or cellular or immune reaction specific to CAP-1002 must also be documented.
时间窗: Within one month of intracoronary infusion
Proportion of subjects that experience ventricular tachycardia or ventricular fibrillation resulting in death, appropriate discharge of an ICD or requiring medical intervention.
时间窗: During or within 72 hours of intracoronary infusion
Proportion of subjects that experience major adverse cardiac events (MACE), including death, non-fatal myocardial infarction and re-hospitalization for cardiovascular event (including heart failure hospitalizations).
时间窗: During or within 72 hours of intracoronary infusion
Proportion of subjects that experience sudden unexpected death occurring within one hour of symptom onset, or un-witnessed death in a person previously observed to be well within the preceding 24 hours without an identified cause.
时间窗: During or within 72 hours of intracoronary infusion
次要结局
- Ventricular tachycardia or ventricular fibrillation resulting in death or requiring medical intervention or appropriate discharge of an ICD.(During the six & twelve month follow-up period)
- Any hospitalization due to a cardiovascular cause or related to CAP-1002 (or placebo in Phase Ib).(During the six & twelve month follow-up period)
- Development of increased anti-Human Leukocyte Antigen (HLA) antibody levels with development of sensitization to HLA antigens specific to the CAP-1002 CDC donor at immunologically significant titers.(During the six & twelve month follow-up period)
- Any inter-current cardiovascular illness or one related to CAP-1002 (or placebo in Phase Ib) which prolongs hospitalization.(During the six & twelve month follow-up period)
- Development of, or an increase in the frequency of, VT with a duration of 30 seconds or longer ascertained by protocol-mandated ECG ambulatory monitoring.(During the six & twelve month follow-up period)
- Total number of appropriate ICD firings.(During the six & twelve month follow-up period)
- Acute myocarditis possibly attributable to CAP-1002. In order to be considered related to CAP-1002, humoral or cellular immune reaction specific to CAP-1002 must also be documented.(During the six & twelve month follow-up period)
- Sudden unexpected death defined as occurring within one hour of symptom onset, or unwitnessed death in a person previously observed to be well within the preceding 24 hours without an identified cause.(During the six & twelve month follow-up period)
- Major adverse cardiac events (MACE), including death, non-fatal myocardial infarction, hospitalization for cardiovascular event, emergency room treatment for heart failure, left ventricular assist device or heart transplant.(During the six & twelve month follow-up period)
- Peak elevation in troponin and CKMB levels following CAP-1002 or placebo infusion.(Through Month 1)