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

• Angina frequency (episodes per week) [ Time Frame: Baseline and 12 months ] [ Designated as safety issue: No ]
  Subjects will self-report angina episodes utilizing an electronic diary for 4 weeks at baseline and before the 3, 6 and 12 month follow-up visit.
• Change from baseline in total exercise time on ETT at the 6 month follow-up timepoint [ Time Frame: Baseline and 6 months ] [ Designated as safety issue: No ]
• Angina frequency (episodes per week) at the 6 month follow-up timepoint [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Incidence of major adverse cardiac events and other serious adverse events in all subjects [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]

• Angina frequency (episodes per week) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  Subjects will self-report angina episodes utilizing an electronic diary for 4 weeks at baseline and before the 3, 6 and 12 month follow-up visit.
• Change from baseline in total exercise time on ETT at the 6 month follow-up timepoint [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Angina frequency (episodes per week) at the 6 month follow-up timepoint [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Incidence of major adverse cardiac events and other serious adverse events in all subjects [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]

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.

• Chronic Myocardial Ischemia
• Refractory Angina Pectoris
• (Advanced) Coronary Heart Disease

• Biological: Auto-CD34+ cells
  10 intramyocardial injections of 0.2 mL per injection site of Auto-CD34+ cells
• Biological: Placebo: Diluent used to suspend Auto-CD34+ cells
  10 intramyocardial injections of 0.2 mL per injection site of placebo
• Other: Standard of care
  Standard of care for refractory angina

• Experimental: Treatment Arm
  Targeted intramyocardial delivery of 1 x 10^5 Auto-CD34+ cells after granulocyte-colony stimulating factor (G-CSF) mobilization and apheresis
  Intervention: Biological: Auto-CD34+ cells
• Placebo Comparator: Active Control Arm
  Targeted intramyocardial delivery of placebo after G-CSF mobilization and apheresis
  Intervention: Biological: Placebo: Diluent used to suspend Auto-CD34+ cells
• Unblinded Standard of Care (SOC) Arm
  No study-related procedures will be performed.
  Intervention: Other: Standard of care

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.