ACT34-CMI -- Adult Autologous CD34+ Cells

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of intramyocardial injections of CLBS14 in patients with refractory chronic myocardial ischemia.

Detailed Description
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This is a double-blind, prospective, randomized, placebo-controlled trial to determine the tolerability, efficacy, safety and dose range of intramyocardial injections of adult autologous CD34+ cells mobilized with granulocyte colony stimulating factor (G-CSF) for the reduction of angina episodes in patients with refractory chronic myocardial ischemia.

Official Title
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A DB, Randomized, Placebo-controlled Study of the Tolerability, Efficacy, Safety, and Dose Range of Intramyocardial CLBS14 for Reduction of Angina Episodes in Patients With Refractory Chronic Myocardial Ischemia (ACT34-CMI)

Conditions
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Myocardial Ischemia

Intervention / Treatment
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* Biological: CLBS14 (low-dose)
* Biological: CLBS14 (high-dose)
* Biological: placebo injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Canadian Cardiovascular Society (CCS) functional class III or IV chronic refractory angina subjects without control of their angina symptoms, in spite of maximal tolerated doses of anti-anginal drugs, must be on optimal therapy for their angina and on a stable anti-anginal medication regimen for at least 1 month prior to entering the screening period of the study identified as unsuitable for conventional revascularization recent coronary angiogram (within the last 12 months) to document the coronary anatomy and to verify the revascularization procedures subjects must have objective evidence of inducible ischemia or viable myocardium in the potential target injection zone a left ventricular ejection fraction equal to or greater than 25% by ECHO or single photon emission computed tomography (SPECT) at screening subjects must experience at minimum an average of 7 angina or anginal equivalent episodes per week subjects must be able to complete a minimum of 3 minutes but nor more than 10 minutes on a treadmill following the Modified Bruce Protocol subjects must experience angina or anginal equivalent episodes during the screening exercise treadmill test female subjects must either be no longer capable of reproduction or using medically valid contraception to prevent pregnancy during the study subjects must be willing and able to comply with specified follow-up evaluations Exclusion Criteria: predominant congestive heart failure myocardial infarction within 60 days of treatment successful or partially successful coronary revascularization procedures (any vessel) within 6 months of study enrollment placement of a bi-ventricular pacemaker for cardiac resynchronization therapy (CRT) for heart failure in the past 90 days documented stroke or transient ischemic attack (TIA) within 60 days of study enrollment history of moderate to severe aortic stenosis or severe aortic insufficiency; severe mitral stenosis or severe mitral insufficiency prosthetic aortic valve replacement evidence of any life-threatening arrhythmia that requires intervention on the 24-hour Holter monitor. Life-threatening arrhythmia that is successfully treated with an implantable cardioverter defibrillator (ICD) is not exclusionary. splenomegaly and/or severe co-morbidity associated with a reduction in life expectancy of less than 1 year, such as chronic medical illness (ie, severe chronic obstructive pulmonary disease, renal failure or cancer [exceptions: in-situ skin cancer or fully removed skin cancer other than melanoma, in-situ cervical cancer, or cancer free for 5 years with no history of a stem cell transplant]) sickle cell disease or sickle cell trait platelet count greater than 10% above the upper limit of normal or a platelet count below 100,000 if on Clopidogrel or 50,000 without Clopidogrel hematocrit <30% serum creatinine >2.5 mg/dL any clinically significant laboratory abnormality on screening laboratories currently enrolled in another IDE or IND that has not completed the protocol required primary follow-up period (excludes 15 year follow up of gene therapy trials) history of alcohol or drug abuse within 3 months of screening joint or peripheral vascular disease or neurologic disease that severely limits treadmill walking chronic obstructive pulmonary disease that severely limits walking or FEV1 <30% predicted females who are pregnant or lactating female subjects who are capable of reproduction and will not use medically valid contraception to prevent pregnancy during the study subjects who test positive for HIV, hepatitis B or hepatitis C, or are on chronic immunosuppressive medications or have had a prior stem cell transplant subjects with a known hypersensitivity to E. coli-derived proteins, or to any component of Neupogen (Filgrastim) or G-CSF subjects who have a significant psychiatric disorder or mental disability that could interfere with the subject´s ability to provide informed consent and/or comply with protocol procedures

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CLBS14: Low-Dose Group<br>10 intramyocardial injections of 0.2 mL each of auto-CD34+ cells at a dose of 1 x 10^5 (=100000) cells/kg bodyweight | Biological: CLBS14 (low-dose)<br>* Eligible subjects will receive subcutaneous injections of 5 µg/kg/day G-CSF for 5 days to mobilize CD34+ cells from the bone marrow to the peripheral blood. Mononuclear cells (MNCs) will be collected via apheresis on day 5. On the day of the cell/placebo injection (day 6), the apheresis product will be enriched for CD34+ cells using the Isolex 300i Magnetic Cell Selection System (Baxter Healthcare). Autologous CD34+ cells will be delivered in 10 intramyocardial injections of 0.2 mL at a dose of 1 x 10^5 (=100000) cells/kg bodyweight each using the MyoStar injection catheter (Biosense Webster, Inc.) into the target areas of myocardial ischemia.<br>* Other names: G-CSF mobilized, autologous CD34+ cells;|
| Experimental: CLBS14: High-Dose Group<br>10 intramyocardial injections of 0.2 mL each of auto-CD34+ cells at a dose of 5 x 10^5 (=500000) cells/kg bodyweight | Biological: CLBS14 (high-dose)<br>* Eligible subjects will receive subcutaneous injections of 5 µg/kg/day G-CSF for 5 days to mobilize CD34+cells from the bone marrow to the peripheral blood. Mononuclear cells (MNCs) will be collected via apheresis on day 5. On the day of the cell/placebo injection (day 6), the apheresis product will be enriched for CD34+ cells using the Isolex 300i Magnetic Cell Selection System (Baxter Healthcare). Autologous CD34+ cells will be delivered in 10 intramyocardial injections of 0.2 mL at a dose of 5 x 10^5 (=500000) cells/kg bodyweight each using the MyoStar injection catheter (Biosense Webster, Inc.) into the target areas of myocardial ischemia.<br>* Other names: G-CSF mobilized, autologous CD34+ cells;|
| Placebo Comparator: Placebo injection<br>10 intramyocardial injections of 0.2 mL each of 0.9% NaCl (saline) in 5% autologous plasma | Biological: placebo injection<br>* Eligible subjects will receive subcutaneous injections of 5 µg/kg/day G-CSF for 5 days to mobilize CD34+ cells from the bone marrow to the peripheral blood. Mononuclear cells (MNCs) will be collected via apheresis on day 5. On the day of the cell/placebo injection (day 6), the apheresis product will be enriched for CD34+ cells using the Isolex 300i Magnetic Cell Selection System (Baxter Healthcare). Placebo will be delivered in 10 intramyocardial injections of 0.2 mL each of 0.9% NaCl (saline) in 5% autologous plasma into the target areas of myocardial ischemia.<br>* Other names: 0.9% NaCl (saline) in 5% autologous plasma;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Angina Episodes Per Week at 6 and 12 Months | The number of angina episodes were collected via an electronic subject diary for four weeks at Baseline and at 6 and 12 months. The four-week angina episodes (per week mean) were used as the frequency for each visit. A lower number represents fewer angina episodes. A lower number is better. | 6 and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exercise Treadmill Test According to Modified Bruce Protocol: Mean Change From Baseline in Duration of Exercise | A modified Bruce Protocol Exercise Treadmill Test was used to evaluate duration of exercise in all subjects. | Change from Baseline to 6 months and change from baseline to 12 months after treatment | 
| Number of Participants With Change in Canadian Cardiovascular Society Anginal Classification Levels | The Canadian Cardiovascular Society (CCS) Functional Classification of Angina is as follows: Class I - Angina only during strenuous or prolonged physical activity Class II - Slight limitation, with angina only during vigorous physical activity Class III - Symptoms with everyday living activities, i.e., moderate limitation Class IV - Inability to perform any activity without angina or angina at rest, i.e., severe limitation | Baseline and 12 months after treatment | 
| Changes From Baseline in Seattle Angina Questionnaire (SAQ) Scores at 6 Months | Angina symptoms were evaluated based on the Seattle Angina Questionnaire (SAQ), which was used to analyze the following: physical limitations, angina stability, angina frequency, treatment satisfaction, and disease perception. The SAQ consisted of 11 questions with 5 or 6 possible responses. Responses were ordinal values (1-7, 10, 11, 97, depending on the type of question; no uniform ranges throughout); responses that corresponded to the lowest level of functioning (worse outcomes) were assigned values of 1, while responses that corresponded to higher functioning levels (better outcome) were assigned a higher ordinal value. If the response to any of these questions was 97 it was recoded as a missing value. Each scale can have a scored value ranging from 0 to 100. A larger number is better. | Baseline to 6 months after treatment | 
| Changes From Baseline to 6 Months in Short Form 36 (SF-36) Parameters | The Short Form 36 (SF-36) health survey form was used to analyze physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, general mental health, and health transition. Responses were coded as ordinal numbers going from worst (=1) to best (=highest number). These ordinal scores were transformed into scales ranging from 0 to 100. Higher numbers are generally considered better. | Baseline to 6 months after treatment | 
| Change in Anti-anginal Medication (ie, Nitroglycerin) Use | The mean nitroglycerin use per week was analyzed at baseline and 6 months | Baseline to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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angina