Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina

Study Overview
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Brief Summary
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The purpose of the study is to assess the safety and efficacy of targeted intramyocardial delivery of Auto-CD34+ cells for increasing exercise time and amelioration of anginal symptoms in subjects with refractory angina and chronic myocardial ischemia.

Official Title
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A Prospective, Randomized, Double-blinded, Active-control and Unblinded Standard of Care (SOC) Controlled Study to Determine the Efficacy and Safety of Targeted Intramyocardial Delivery of Autologous CD34+ Cells (Auto-CD34+ Cells) for Increasing Exercise Capacity During Standardized Exercise Testing in Subjects With Refractory Angina Pectoris and Chronic Myocardial Ischemia

Conditions
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Chronic Myocardial Ischemia, Refractory Angina Pectoris, Advanced Coronary Heart Disease

Intervention / Treatment
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* Biological: Auto-CD34+ cells
* Biological: Placebo: Diluent used to suspend Auto-CD34+ cells
* Other: Standard of care


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Male or female participants who are 21 to 80 years of age at the time of signing the informed consent. Participants with Canadian Cardiovascular Society (CCS) class III or IV chronic refractory angina. Participants without control of their angina symptoms in spite of maximal tolerated doses of anti-angina drugs. Participants must be on optimal therapy for their angina and must have been on a stable anti-anginal medication regimen for at least 4 weeks before signing the informed consent form. Participants with obstructive coronary disease unsuitable for conventional revascularization due to unsuitable anatomy or comorbidity as determined at the site and confirmed by an independent adjudication committee. Participants must have evidence of inducible myocardial ischemia. Participants must experience angina episodes. Participants must be able to complete 2 exercise tolerance tests on the treadmill within 3 weeks of randomization. If female of childbearing potential, subject must not be pregnant and agree to employ adequate birth control measures for the duration of the study. Main Exclusion Criteria: Cardiovascular hospitalization within 60 days prior to potential study enrollment. Participant has had a successful or partially successful coronary artery bypass graft (CABG) within 6 months or PCTA within 60 days of potential study enrollment. Participant has had a placement of a bi-ventricular pacemaker for cardiac resynchronization therapy (CRT) for heart failure within 180 days of potential study enrollment. Participant has documented stroke or transient ischemic attacks (TIAs) within 60 days of potential study enrollment. Participant has a history of moderate to severe aortic stenosis; or severe aortic insufficiency; or severe mitral stenosis; or severe mitral insufficiency. Participant has a prosthetic aortic valve or a mechanical mitral valve replacement. Participant has severe co-morbidity associated with a reduction in life expectancy to less than 3 years as a result of chronic medical illnesses. Participants with cancer are excluded with the following exceptions: Subjects with in-situ non-melanoma skin cancer or in-situ cervical cancer are not excluded. Participants that have been cancer free for >= 5 years as determined by their oncologist are not excluded. Subjects with a prior history of stem cell transplant for cancer are excluded no matter how long they have been cancer-free. Participants with a history of leukemia or other bone marrow disease. Participant has sickle cell disease or sickle cell trait. Participants with proliferative retinopathy. Participants with Hb A1c > 9%. Participant has platelet counts >10% above the upper limit of normal (ULN) or platelet counts < 70,000. Participant has a hematocrit < 30% prior to potential study enrollment. Participant has a serum creatinine > 2.5 mg/dL prior to potential study enrollment. Participant tests positive for HIV, hepatitis B, or hepatitis C, or is on chronic immunosuppressive medications, or has had a previous stem cell transplant. Participant has a known contraindication to Neupogen (filgrastim) or G-CSF. Participant was previously enrolled in an active treatment group of cell therapy trials for cardiovascular disease including any phase of CD34+ stem cell trials. Left ventricular (LV) thickness of < 7 mm in the target areas of injection as measured by during a 2-D echocardiogram (ECHO). Atrial fibrillation, atrial flutter, or other uncontrolled arrhythmias that would prohibit accurate electromechanical mapping and NOGA-guided intramyocardial injection. Bleeding diathesis with an INR > 1.8 when not receiving anti-thrombotic therapy. Hepatic dysfunction as evidenced by elevated AST or ALT levels > 2.5 x ULN. Any previous transplant requiring immunosuppression. Disease state requiring chronic immunosuppression.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>Targeted intramyocardial delivery of 1 x 10^5 Auto-CD34+ cells after granulocyte-colony stimulating factor (G-CSF) mobilization and apheresis | Biological: Auto-CD34+ cells<br>* 10 intramyocardial injections of 0.2 mL per injection site of Auto-CD34+ cells<br>|
| Placebo Comparator: Active Control Arm<br>Targeted intramyocardial delivery of placebo after G-CSF mobilization and apheresis | Biological: Placebo: Diluent used to suspend Auto-CD34+ cells<br>* 10 intramyocardial injections of 0.2 mL per injection site of placebo<br>|
| Other: Unblinded Standard of Care (SOC) Arm<br>No study-related procedures will be performed. | Other: Standard of care<br>* Standard of care for refractory angina<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Total Exercise Time on Exercise Tolerance Test (ETT) Using the Modified Bruce Protocol | Baseline (BL) is the average of the two total exercise times measured during the screening period. | Baseline and 12 month visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Incidences of MACE From Randomization Until the End of the 24 Month Follow-up Period | Major adverse cardiac events (MACE) defined as death, cardiac hospitalization, non-fatal myocardial infarction and stroke, as adjudicated by an independent clinical endpoint classification (CEC) committee. The category Total MACE includes death, cardiovascular hospitalization, myocardial infarction or stroke. | From randomization until the end of the 24 month follow-up period | 
| Percentage of Participants With at Least One Serious Adverse Event (SAE) From Randomization Until the End of the 24 Month Follow-up Period |  | From randomization until the end of the 24 month follow-up period | 
| Angina Frequency (Episodes Per Week) at the 12 Month Follow-up Visit | Participants self-reported angina episodes utilizing an electronic diary for 4 weeks at baseline (screening period) and in the 4 weeks before the 3, 6 and 12 month follow-up visits. | Baseline and 12 month visit | 
| Change From Baseline in Total Exercise Time on Exercise Tolerance Test (ETT) at the 6 Month Follow-up Visit | Baseline (BL) is the average of the two total exercise times measured during the screening period. | Baseline and 6 month visit | 
| Angina Frequency (Episodes Per Week) at the 6 Month Follow-up Visit |  | 6 month visit |